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Faculty
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Read More about Irfan A. Asangani, Ph.D.Irfan A. Asangani, Ph.D.
Associate Professor
Irfan A. Asangani, Ph.D.
Associate Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Blvd, 611 BRB II/III
Philadelphia PA, 19104-6160
T: 215-746-8780 F: 215-573-6725
Education
B.S. (Biochemistry) Madras University, 1999
M.S. (Biochemistry) Madras University, 2001
Ph.D. (Cancer Biology) Klinikum Mannheim / DKFZ / Heidelberg University, 2009
Links
Current Research
Prostate cancer is the most common non-cutaneous malignancy and second leading cause of cancer-related mortality in men of the Western world. While effective surgical, radiation, and androgen ablation therapy exists for clinically localized prostate cancer, progression to metastatic castration-resistant prostate cancer (CRPC) remains essentially incurable. Despite the success of recently approved therapies targeting AR (androgen receptor) signaling, durable responses are limited due to acquired resistance. Therefore, the identification and therapeutic targeting of co-activators or mediators of AR transcriptional signaling should be considered as alternate strategies to treat CRPC. Our research is focused on chromatin modifying enzymes and chromatin-associated epigenetic regulator proteins in the context of prostate cancer initiation and progression to metastasis.
Current areas of interest within the laboratory include:
1. Delineating the role of chromatin regulators, and its importance in AR mediated transcription
2. Understanding the role of non-coding RNA in regulating higher order chromatin structure
3. Investigate the molecular mechanisms of resistance to targeted therapiesAsangani Lab
Cancer cells display an altered landscape of chromatin leading to broad changes in the gene expression. In addition, genes involved in chromatin remodeling and epigenetic regulation are frequently and specifically mutated in a wide variety of cancers including prostate cancer. While known to serve important roles in the control of gene expression and development, these largely unexpected mutation findings have illuminated newly recognized mechanisms central to the genesis of cancer. Gaining insight into the mechanism of chromatin regulation in cancer will offer the potential to reveal novel approaches and targets for effective therapeutic intervention.
Our laboratory employs a multidisciplinary approach to study these molecular epigenetic events associated with cancer towards the overarching goal of translating this knowledge into clinical tools by developing novel diagnostic, prognostic and therapeutic strategies. Additionally, we investigate the mechanisms of resistance to targeted therapies and develop novel combinatorial approaches that act on compensatory/new pathways in resistant tumors. Our basic strategy is to develop and deploy rational polytherapy upfront that suppresses the survival and emergence of resistant tumor cells.
Postdoctoral positions are available for highly talented and motivated cancer biologists to join the Asangani laboratory. Ideal candidates will have an interest/experience in cancer epigenetics or metastasis, though extremely qualified candidates of any background in biology will be considered. Applicants must be near completion or have recently completed a Ph.D. Interested candidates should contact Dr. Asangani directly at asangani@upenn.edu and include CV, research summary, and three references.Selected Publications
01. Rasool RU, Natesan R, Deng Q, Aras S, Lal P, Sander Effron S, Mitchell-Velasquez E, Posimo JM, Carskadon S, Baca SC, Pomerantz MM, Siddiqui J, Schwartz LE, Lee DJ, Palanisamy N, Narla G, Den RB, Freedman ML, Brady DC, Asangani IA. CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation. Cancer Discovery. 2019 Aug, 10.1158/2159-8290 CD-19-0189. Epub ahead of print
02. Gollavilli PN, Pawar A, Wilder-Romans K, Natesan R, Engelke CG, Dommeti VL, Krishnamurthy PM, Nallasivam A, Apel IJ, Xu T, Qin ZS, Feng FY, Asangani IA EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins. Cancer Res. 2018 Aug 15;78(16):4760-4773. doi: 10.1158/0008-5472.CAN-18-0484. Epub 2018 Jun 13.
03. Pawar A., Gollavilli P.N, Wang S., Asangani I.A. Resistance to BET inhibitor leads to alternative therapeutic vulnerabilities in castration-resistant prostate cancer. Cell Reports. 2018 Feb 27;22(9):2236-2245.
04. Wang X, Qiao Y., Asangani I.A., Ateeq B, Poliakov A., Cieslik M., Pitchiaya S., Chakravarthi B.V., Cao X., Jing X., Wang C.X., Apel I.J., Wang R., Tien J.C., Juckette K.M., Yan W., Jiang H., Wang S., Varambally S., Chinnaiyan A.M. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer Cancer Cell. 2017 Mar 16. pii: S1535-6108(17)30060-0. doi: 10.1016/j.ccell.2017.02.017. [Epub ahead of print]
05. Malik R., Khan A.P., Asangani I.A., Cieslik M., Prensner J.R., Wang X., Iyer M.K., Xia Jiang1,2, Borkin D., Escara-Wilke J., Wu Y.M., Niknafs Y.S, Jing X., Qiao Y., Palanisamy N., Kunju L.P., Krishnamurthy P.M., Mellacheruvu D., Nesvizhskii A.I., Cao X., Dhanasekaran S.M., Feng F.Y., Grembecka J., Cierpicki T., Chinnaiyan A.M. Targeting the MLL complex in castration resistant prostate cancer. Nat. Med. 2015 Mar 30. doi: 10.1038/nm.3830.
06. Asangani I.A., Dommeti V.L., Wang X., Malik R., Cieslik M., Yang R., Escara-Wilke J., Wilder-Romans K., Dhanireddy S., Engelke C., Iyer M.K., Jing X., Wu Y.M., Cao X., Qin Z.S., Wang S., Feng F.Y., Chinnaiyan A.M. Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer. Nature. 2014 Jun 12;510(7504):278-82. doi: 10.1038/nature13229.
07. Asangani I.A., Ateeq B., Cao Q., Dodson L., Pandhi M., Kunju L.P., Mehra R., Lonigro R.J., Siddiqui J., Palanisamy N., Wu Y.M., Cao X., 07. Kim J.H., Zhao M., Qin Z.S., Iyer M.K., Maher C.A., Kumar-Sinha C., Varambally S., Chinnaiyan AM. Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer. Mol Cell. 2013 Jan 10;49(1):80-93. doi: 10.1016/j.molcel.2012.10.008.
08. Prensner J.R., Iyer M.K., Sahu A., Asangani I.A., Cao Q., Patel L., Vergara I.A., Davicioni E., Erho N., Ghadessi M., Jenkins R.B., Triche T.J., Malik R., Bedenis R., McGregor N., Chen W., Han S., Jing X., Cao X., Wang X., Chandler B., Yan W., Siddiqui J., Kunju L.P., Dhanasekaran S.M., Pienta K.J., Feng F.Y., Chinnaiyan
A.M. The lncRNA SChLAP1 coordinates aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013 Nov;45(11):1392-8. doi: 10.1038/ng.2771.
09. Grasso C.S., Wu Y.M., Robinson D.R., Cao X., Dhanasekaran S.M., Khan A.P., Quist M.J., Jing X., Lonigro R.J., Brenner J.C., Asangani I.A., Ateeq B., Chun S.Y., Siddiqui J., Sam L., Anstett M., Mehra R., Prensner J.R., Palanisamy N., Ryslik G.A., Vandin F., Raphael B.J., Kunju L.P., Rhodes D.R., Pienta K.J., Chinnaiyan A.M., Tomlins S.A. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012 Jul 12;487(7406):239-43. doi: 10.1038/nature11125.
10. Cao Q., Mani R.S., Ateeq B., Dhanasekaran S.M., Asangani I.A., Prensner J.R., Kim J.H., Brenner J.C., Jing X., Cao X., Wang R., Li Y., Dahiya A., Wang L., Pandhi M., Lonigro R.J., Wu Y.M., Tomlins S.A., Palanisamy N., Qin Z., Yu J., Maher C.A., Varambally S., Chinnaiyan A.M. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011 Aug 16;20(2):187-99. doi: 10.1016/j.ccr.2011.06.016.
11. Brenner J.C., Ateeq B., Li Y., Yocum A.K., Cao Q., Asangani I.A., Patel S., Wang X., Liang H., Yu J., Palanisamy N., Siddiqui J., Yan W., Cao X., Mehra R., Sabolch A., Basrur V., Lonigro R.J., Yang J., Tomlins S.A., Maher C.A., Elenitoba-Johnson K.S., Hussain M., Navone N.M., Pienta K.J., Varambally S., Feng F.Y., Chinnaiyan A.M. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011 May 17;19(5):664-78. doi: 10.1016/j.ccr.2011.04.010. Erratum in: Cancer Cell. 2013 Apr 15;23(4):557.
12. Asangani I.A., Rasheed S.A., Nikolova D.A., Leupold J.H., Colburn N.H., Post S., Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008 Apr 3;27(15):2128-36. Featured article.
Lab Personnel
Chandan Das - Postdoctoral Researcher
Erick Mitchell-Velásquez - Ph.D. Student
Reyaz Ur Rasool - Postdoctoral Researcher
Deb Sneddon - Program Coordinator dsneddon@upenn.edu
Brijesh Kumar Verma - Postdoctoral Researcher
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Read More about Bobby Bowman, Ph.D.Bobby Bowman, Ph.D.
Assistant Professor
Bobby Bowman, Ph.D.
Assistant Professor
Department of Cancer Biology and Medicine
Assistant Investigator, Abramson Family Cancer Research Institute
Contact Information
421 Curie Blvd., 753 BRB II/III
Philadelphia, PA 19104-6160
Office: 215-746-0921
robert.bowman@pennmedicine.upenn.edu
Education
B.A. (Molecular Cellular Biology) Vanderbilt University 2010
PhD (Cancer Biology) Gerstner Sloan Kettering 2016
Links
Current Research
We are interested in studying the evolution of cancer development from pre-malignancy through transformation. Hematologic malignancies are an ideal disease model to study classical questions in cancer biology, given sample access and extensive description of the normal hematopoietic differentiation cascade. Genetic studies in acute myeloid leukemia (AML) have revealed a hierarchical arrangement of mutations such that certain mutations are postulated to be acquired either early or late in disease progression. This stepwise acquisition of mutations results in a genetically heterogeneous collection of clones contributing to disease development. Through the progression from pre-malignancy to leukemic transformation, we study the following broad questions:
1) What are the necessary steps for a mutant cell to transform to leukemia?
2) After transformation, how do leukemic cells affect normal non-mutated cells?
3) How can we revert or halt transformed cells early in disease development to prevent disease development?
We approach these questions through an intersection of genomic profiling of patient samples and synthetic biology approaches for modeling disease in mice
Bowman Lab
The major focus of the lab is on the receptor tyrosine kinase, FLT3, which is the most commonly mutated gene in AML and typically presents as a subclonal, late event. Mutations can manifest as internal tandem duplications (ITDs) in the juxtamembrane domain leading to constitutive kinase activation. Despite being mutated in only a subset of leukemic cells, FLT3 mutations are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs e.g. gilteritinib) demonstrate substantive clinical efficacy, but invariably lead to relapse. It remains unclear when a given leukemia is dependent upon FLT3 mutations, and how a subclonal oncogene portends such poor prognosis yet has therapeutic utility. In a broader context, understanding the functional roles of clonal and subclonal mutations in AML initiation and maintenance has fundamental mechanistic and therapeutic implications. Current projects in the lab focus on:
1: Oncogenic dependency in leukemic stem cells We will seek to understand how quiescent leukemic stem cells respond to therapy by juxtaposing chemical vs genetic inhibition. In the long term seek to understand how cooperating mutations influence the quantity and characteristics of this stem cell pool.
2: Evaluating cell of origin in FLT3-driven acute myeloid leukemia. We hypothesize that different cooperating mutations influence the cell of origin of FLT3 driven disease. Our lab will approach this question using inducible mouse models and synthetic biology approaches for cell type specific control. In the long term, we seek to progress towards complete in vivo modeling through the development of novel cell type specific recombinase mouse lines.
3 : Investigate interclonal interactions in leukemic progression. We hypothesize that this stepwise acquisition of mutations results in a genetically diverse ecosystem where clones interact either in supporting or suppressing other genetically distinct clones. Our group will investigate inter-clonal interactions and competition through the lens of FLT3 mutant AML, investigating several key questions including: Does the presence of a FLT3-mutant clone affect the fitness of antecedent clones? To investigate clonal heterogeneity and paracrine interactions we will integrate single cell genomic profiling in clinical isolates and mouse models of subclonal FLT3-mutations, mechanistically evaluate candidate paracrine factors ex vivo, and evaluate their role in disease progression in vivo.
Selected Publications
01. Bowman RL, Dunbar A, Mishra T, Xiao W, Waarts MR, Fernández Maestre I, Eisman SE, Cai L, Cai SF, Sanchez Vela P, Mowla S, Martinez Benitez AR, Park Y, Csete IS, Krishnan A, Lee D, Boorady N, Potts CR, Jenkins MT, Carroll MP, Meyer SE, Miles LA, Ferrell PB, Trowbridge JJ, Levine RL. Modeling clonal evolution and oncogenic dependency in vivo in the context of hematopoietic transformation. BioRxiv 492524 [Preprint]. May 18, 2022 [cited 2023 April 29]. Available from: https://doi.org/10.1101/2022.05.18.492524
02. Waarts MR, Mowla S, Boileau M, Martinez Benitez AR, Sango J, Bagish M, Fernandez-Maestre I, Shan Y, Eisman SE, Park YC, Wereski M, Csete I, O'Connor K, Romero-Vega AC, Miles LA, Xiao W, Wu X, Koche RP, Armstrong SA, Shih AH, Papapetrou EP, Butler JM, Cai SF, Bowman RL, Levine RL. CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells. Cancer Discovery. 2024 May 31. doi: 10.1158/2159-8290.CD-23-1092.
03. Dunbar AJ*, Bowman RL*, Park YC, O'Connor K, Izzo F, Myers RM, Karzai A, Zaroogian Z, Kim WJ, Fernandez-Maestre I, Waarts MR, Nazir A, Xiao W, Codilupi T, Brodsky M, Farina M, Cai L, Cai SF, Wang B, An W, Yang JL, Mowla S, Eisman SE, Hanasoge Somasundara AV, Glass JL, Mishra T, Houston R, Guzzardi E, Martinez Benitez AR, Viny AD, Koche RP, Meyer SC, Landau DA, Levine RL. Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms. Cancer Discovy. 2024 Jan 12. doi: 10.1158/2159-8290.CD-22-0952.
04. Miles LA*, Bowman RL*, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, Bowman M, Famulare C, Patel MA, Mendez P, Ainali C, Demaree B, Delley CL, Abate AR, Manivannan M, Sahu S, Goldberg AD, Bolton KL, Zehir A, Rampal R, Carroll MP, Meyer SE, Viny AD, Levine RL.: Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587(7834): 477-482, 2020 Notes: DOI: 10.1038/s41586-020-2864-x.
05. Robert L. Bowman, Andrew Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R. Waarts, Inés Fernández Maestre, Shira E. Eisman, Louise Cai, Sheng F. Cai, Pablo Sanchez Vela, Shoron Mowla, Anthony R. Martinez Benitez, Young Park, Isabelle S. Csete, Aishwarya Krishnan, Darren Lee, Nayla Boorady, Chad R. Potts, Matthew T. Jenkins, Martin P. Carroll, Sara E. Meyer, Linde A. Miles, P. Brent Ferrell Jr., Jennifer J. Trowbridge, Ross L. Levine. Modeling clonal evolution and oncogenic dependency in vivo in the context of hematopoietic transformation. bioRxiv 2022.05.18.492524; doi: https://doi.org/10.1101/2022.05.18.492524
06. Andrew Dunbar, Robert L. Bowman, Young Park, Franco Izzo, Robert M. Myers, Abdul Karzai, Won Jun Kim, Inés Fernández Maestre, Michael R. Waarts, Abbas Nazir, Wenbin Xiao, Max Brodsky, Mirko Farina, Louise Cai, Sheng F. Cai, Benjamin Wang, Wenbin An, Julie L Yang, Shoron Mowla, Shira E. Eisman, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R. Martinez Benitez, Aaron Viny, Richard Koche, Dan A. Landau, Ross L. Levine. Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasm. bioRxiv 2022.05.18.492332; doi: https://doi.org/10.1101/2022.05.18.492332
07. Miles LA*, Bowman RL*, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, Bowman M, Famulare C, Patel MA, Mendez P, Ainali C, Demaree B, Delley CL, Abate AR, Manivannan M, Sahu S, Goldberg AD, Bolton KL, Zehir A, Rampal R, Carroll MP, Meyer SE, Viny AD, Levine RL. "Single-cell mutation analysis of clonal evolution in myeloid malignancies." Nature. 2020 Nov;587(7834):477-482.
08. Bowman RL, Busque L, Levine RL. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies." Cell Stem Cell. 2018 Feb 1;22(2):157-170.
Lab Personnel
Lesley Moreno, Administrative Assistant
Nisarg Shah - Research Specialist D
Angela Youn - Research Specialist A
Michael Bowman PhD - Postdoctoral Researcher
Roopsha Bandopadhyay - PhD Student – Bioengineering
Anushka Gandhi - Undergraduate Researcher
Shreeya Gounder - Undergraduate Researcher
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Read More about Donita C. Brady, Ph.D.Donita C. Brady, Ph.D.
Presidential Associate Professor and Vice Chair for Inclusion and Equity
Donita C. Brady, Ph.D.
Presidential Associate Professor and Vice Chair for Inclusion and Equity
Harrison McCrea Dickson, M.D. and Clifford C. Baker, M.D. Presidential Associate Professor
Vice Chair for Inclusion and Equity
Assistant Dean for Inclusion, Diversity, and Equity in Research Training
Associate Investigator, Abramson Family Cancer Research Institute
Member, Abramson Cancer Center Tumor Biology Program
Contact Info
421 Curie Boulevard, 612 BRB II/III
Philadelphia PA, 19104-6160
T: 215-573-9705 F: 215-573-6725
Education
B.S. (Chemistry) Radford University, 2003
Ph.D. (Pharmacology) University of North Carolina at Chapel Hill, 2008
Links
Research Interests
Our research program at Penn is founded in a new paradigm in nutrient sensing and protein regulation, termed metalloallostery, where redox-active metals control kinase activity, and is advancing our knowledge in basic science and disease-focused areas. Our focus lies at the intersection of kinase signaling and copper (Cu) homeostasis with the goal of defining the mechanistic features of Cu-dependent kinases to target them in cancer via drug repurposing or development. Kinases directly respond to and, in some cases, sense inputs, like growth factors, nutrients, and metabolites, to relay information to drive complex cellular processes. Aberrant kinase activation disrupts the balance between cell growth and cell death and in turn, can drive cancer initiation and progression. While kinase inhibitors dramatically changed the landscape of cancer treatment, emergence of resistance limits clinical durability. Our discovery that the transition metal Cu, which is acquired as a dietary nutrient and essential for life, activates the canonical MAPK pathway at the level of the MEK1/2 kinases established an evolutionarily conserved, critical mechanistic function for Cu as an intracellular mediator of signaling (Turski & Brady et al. Mol Cell Biol 2012). The direct interaction between Cu and MEK1/2 is the first example of Cu enhancing mammalian kinase activity and exposed a mechanistically distinct vulnerability that can be exploited therapeutically in cancers with aberrant MAPK signaling (Brady et al. Nature 2014). The emergence of this new clinically relevant signaling paradigm highlights the need to understand how redox-active metals interact with signaling pathways and underlines the promise of discovering new modes of kinase regulation as orthogonal therapeutic vulnerabilities.
Selected Publications
01. Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, Knapp S, Xiao K, Campbell SL, Thiele DJ, Counter CM. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509(7501): 492-496, May 2014.
02. Turski ML*, Brady DC*, Kim HJ, Kim BE, Nose Y, Counter CM, Winge DR, Thiele DJ. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Molecular and Cellular Biology 32(7): 1284-1295, Apr 2012.
03. Kashatus DF, Lim KH, Brady DC, Pershing NLK, Cox AD, Counter CM. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature Cell Biology 13(9): 1108-1115, Sep 2011.
04. Zipfel PA, Brady DC, Kashatus DF, Ancrile BD, Tyler DS*, Counter CM*. Ral activation promotes melanomagenesis. Oncogene 29(34): 4859-4864, Aug 2010.
05. Lim KH*, Brady DC*, Kashatus DF, Ancrile BB, Der CJ, Cox AD*, Counter CM*. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Molecular and Cellular Biology 30(2): 508-523, Jan 2010.
06. O'Hayer KM, Brady DC, Counter CM. ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis. Carcinogenesis 30(11): 1841-1847, Nov 2009.
07. Madigan JP, Bodemann BO, Brady DC, Dewar BJ, Keller PJ, Leitges M, Philips MR, Ridley AJ, Der CJ, Cox AD. Regulation of Rnd3 localization and function by protein kinase C alpha-mediated phosphorylation. The Biochemical Journal 424(1): 153-161, Nov 2009.
08. Brady DC, Alan JK, Madigan JP, Fanning AS, Cox AD. The transforming Rho family GTPase Wrch-1 disrupts epithelial cell tight junctions and epithelial morphogenesis. Molecular and Cellular Biology 29(4): 1035-1049, Feb 2009.
09. Sammons S, Brady DC, Vahdat LT, & Salama AKS. Copper suppression as a cancer therapy: the rationale for copper chelating agents in BRAFV600 mutated melanoma. Melanoma Manag, In Press (2016).
10. Chen HY, Brady DC, & Villanueva J. Double Trouble: Kinase domain duplication as a new path to drug resistance. Pigment Cell Melanoma Res, In Press (2016).
Lab Personnel
Arlene Abreu - Graduate Student
Santanu Ghosh - Postdoctoral Researcher
Andrew Jarvis - Research Specialist
Le Shou - Postdoctoral Researcher
Deb Sneddon - Program Coordinator dsneddon@upenn.edu
Ralph White III - Postdoctoral Researcher
Rotation Students
Islam Elsaid, Graduate Student
Kim Manning, Graduate Student
Nate McNight, Graduate Student
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Read More about Eric J. Brown, Ph.D.Eric J. Brown, Ph.D.
Associate Professor
Eric J. Brown, Ph.D.
Associate Professor
Associate Investigator and Director of Education, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 514 BRB II/III
Philadelphia PA, 19104-6160
T: 215-746-2805 F: 215-573-6725
Education
B.A. (Genetics) University of California at Berkeley, 1989
Ph.D. (Immunology) Harvard University, 1996
Links
Current Research
Maintenance of genome integrity plays a critical role in the prevention of cancer and other age-associated diseases. My laboratory studies the mechanisms utilized to safeguard the genome and investigates how failures in these processes impact tissue homoeostasis, cancer risk, and, potentially, cancer treatments. We are particularly interested in processes that maintain genome stability during DNA replication.
Brown Lab
As an essential sensor of problems occurring during DNA replication, the ATR protein kinase regulates a signal transduction cascade that preserves troubled DNA replication forks and prevents their collapse into DNA double strand breaks. The conditions that activate the ATR pathway during DNA replication include oncogenic stress, replisome dysfunction, and encounters with difficult-to-replicate DNA sequences and naturally occurring forms of DNA damage. In aggregate, such problems are relatively common. Thus, ATR pathway, as a component of a multilayered network of DNA replication and repair factors, performs an essential function in genome maintenance that influences the emergence of cancer and other age-associated diseases. Using both mouse models and cell-based systems, we are currently investigating how the ATR pathway counters replicative stress, how replication stress relates to the process of aging, and whether hypomorphic suppression of the ATR pathway may serve as an effective cancer treatment.
Selected Publications
R. S. Rivard, Y-C Chang, R. L. Ragland, Y-M Thu, S. K. Van Ripper, K. Kulej, L. Higgins, T. Markowski, D. Shang, J. Hedberg, L. Erber, B. Garcia, Y. Chen, A-K. Bielinsky and E. J. Brown (2024). A method for improved detection of DNA replication fork-associated proteins. Cell Reports 43, 114178. PMID: 38703364, PMCID: in process.
H. Small, J. Tang, Y. Ruzankina, D. W. Schoppy, M. R. Glineburg, Z. Ustelenca, D. Powell, F. Simpkins, F. B. Johnson, and E. J. Brown (2022). Induction of Interleukin-19 through JNK and cGAS-STING modulates DNA-damage-induced cytokine expression. Sci Signal 14 (714), DOI: 10.1126/scisignal.aba2611.
H. Xu, E. George, Y. Kinose, H. Kim, J. B. Shah, J. D. Peake, B. Ferman, S. Medvedev, T. Murtha, C. J. Barger, K. M. Devins, K. D’Andrea, B. Wubbenhorst, L. E. Schwartz, W.-T. Hwang, G. B. Mills, K. L. Nathanson, A. R. Karpf, R. Drapkin, E. J. Brown and F. Simpkins (2021). CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models. Cell Reports Med 2, 100394.
H. Kim, H. Xu, E. George, D. Hallberg, S. Kumar, V. Jagannathan, S. Medvedev, Y. Kinose, K . Devins, P. Verma, K. Ly, Y. Wang, R. A. Greenberg, L. Schwartz, N. Johnson, R. B. Scharpf, G. B. Mills, R. Zhang, V. E. Velculescu, E. J. Brown and F. Simpkins (2020). Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 11, 3726-3742. PMCID: PMC7381609
N. Shastri, Y-C Tsai, S. Hile, D. Jordan, B. Powell, J. Chen, D. Maloney, M. Dose, Y. Lo, T. Anastassiadis, O. Rivera, T. Kim, S. Shah, P. Borole, K. Asija, X. Wang, K. D. Smith, D. Finn, J. Schug, R. Casellas, L. A. Yatsunyk, K. A. Eckert and E. J. Brown (2018). Genome-wide identification of structure-forming repeats as principal sites of fork collapse upon ATR inhibition. Mol Cell, 72, 222-238. PMCID: PMC6407864
R. L. Ragland, S. Patel, R. S. Rivard, K. D. Smith, A. A. Peters, A.-K. Bielinsky and E. J. Brown (2013). RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev, 27, 2259-2273. PMCID: PMC24142876
D. W. Schoppy, R. L. Ragland, O. Gilad, N. Shastri, A. A. Peters, M. Murga, O. Fernandez-Capetillo, J. A. Diehl and E. J. Brown (2012). Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122, 241-252. PMCID: PMC3248295
Gilad O, Nabet BY, Ragland RL, Schoppy DW, Smith KD, Durham AC, Brown EJ. Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Research 70 (23), 2010. PMID: 21098704. PMCID: PMC3057927.
Ruzankina Y, Schoppy DW, Asare A, Clark CE, Vonderheide RH, Brown E.J.: Tissue regenerative delays and synthetic lethality in adult mice upon combined deletion of ATR and p53. Nature Genetics 41(10): 1144-1149, 2009. PMID: 19718024. PMCID: PMC2823374
Smith KD, Fu MA, Brown EJ. Tim-Tipin dysfunction creates an indispensible reliance on the ATR-Chk1 pathway for continued DNA synthesis. The Journal of Cell Biology 187(1): 15-23, 2009. PMID: 19805627. PMCID: PMC2762102.
Lab Personnel
Heather Birmingham, Administrative Assistant
Muzaffer Kassab - Senior Research Investigator
Rahul Mandal - Research Associate
Ibnat Meah – Research Assistant
Isa Andrade - Research Assistant
Sophie Kudler - Research Assistant
Henry Zabierek - Research Assistant
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Read More about Luca Busino, Ph.D.Luca Busino, Ph.D.
Associate Professor
Luca Busino, Ph.D.
Associate Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 705 BRB II/III
Philadelphia PA, 19104
T: 215-746-2569
Education
B.S. (Medical Biotechnology) Università di Napoli Federico II, 2001
Ph.D. (Experimental Oncology) European Institute of Oncology, 2007
Links
Current Research
My laboratory studies the mechanisms by which the ubiquitin-proteasome system (UPS) controls cell proliferation and how alterations in these processes contribute to tumor initiation and maintenance. Misregulation of protein degradation pathways is often observed in cancer cells. Integrating the study of cellular signals with the molecular mechanisms by which ubiquitin ligases target substrates will advance our knowledge of cancer biology and will provide novel avenues for development of therapeutics.
Areas of interest within the laboratory include, but are not limited to: (i) Signaling Pathways (such as those related to the cell division cycle, DNA damage response, circadian clock, and NFkB signaling) and (ii) Identification of small molecules to target ubiquitin ligases.Busino Lab
Hematological malignancies are tumors that affect blood, bone marrow and lymph nodes. Taken together, hematological malignancies account for approximately 10% of new cancer diagnoses in the United States. Drugs that target the UPS, such as thalidomide and bortezomib, improve survival, underlining the effectiveness of targeting the UPS, but resistance to these therapies eventually develops. Therefore, the identification of novel UPS enzymes that could serve as targets is crucial for the development of therapeutics.
My laboratory focuses on two main research areas:
(i) Functional discoveries in the area of ubiquitin system and hematologic diseases.
This research area aims to characterize the molecular functions of cancer associated-mutant ubiquitin ligases. Our lab combines genetic and proteomic-based approaches to identify and elucidate novel substrate-ligase pairings and their biological significance in sustaining the proliferation of cancer B-cells.
(ii) Development of high-throughput assays to identify small molecules targeting ubiquitin ligase-substrate interactions.
With this research area, we aim to establish assays to serve as a screening platform for targeting specific ligase-substrate interactions. Our long-term goal is to identify candidate molecules to test them in models of leukemia and lymphoma.Selected Publications
Aqsa YashfeenDCAF15 control of cohesin dynamics sustains acute myeloid leukemia. Grothusen GP, Chang R, Cao Z, Zhou N, Mittal M, Datta A, Wulfridge P, Beer T, Wang B, Zheng N, Tang HY, Sarma K, Greenberg RA, Shi J, Busino L. Nat Commun. 2024 Jul 3;15(1):5604. doi: 10.1038/s41467-024-49882-x.PMID: 38961054 Free PMC article.
A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins.Islam S, Gour J, Beer T, Tang HY, Cassel J, Salvino JM, Busino L. ACS Chem Biol. 2024 Feb 16;19(2):233-242. doi: 10.1021/acschembio.3c00570. Epub 2024 Jan 25. PMID: 38271588
Zhou N, Choi J, Grothusen G, Kim BJ, Ren D, Cao Z, Liu Y, Li Q, Inamdar A, Beer T, Tang HY, Perkey E, Maillard I, Bonasio R, Shi J, Ruella M, Wan L, Busino L. DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood. 2023 Sep 14;142(11):973-988.
Simoneschi D, Rona G, Zhou N, Jeong YT, Jiang S, Milletti G, Arbini AA, O'Sullivan A, Wang AA, Nithikasem S, Keegan S, Siu Y, Cianfanelli V, Maiani E, Nazio F, Cecconi F, Boccalatte F, Fenyö D, Jones DR, Busino L*, Pagano M* (*co-last and co-corresponding authors): CRL4-AMBRA1 is a master regulator of D-type cyclins. Nature 592(7856): 789-793, April 2021.
Saffie R, Rolland DCM, Onder O, Basrur V, Elenitoba-Johnson KSJ, Capell BC, Busino L: FBXW7 triggers degradation of KMT2D to favor growth of mature B-type malignant cells. Cancer Research 80(12): 2498-2511, June 2020.
Guillamot M, Ouazia D, Dolgalev I, Kourtis N, Dai Y, Corrigan K, Yeung S, Zea-Redondo L, Saraf A, Florens L, Washburn MP, Tikhonova AN, Gong Y, Tsirigos A, Park C, Barbieri C, Khanna K, Busino L*, Aifantis I* (*co-last and co-corresponding authors): The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MyD88 degradation. Nature Immunology 20(9): 1196-1207, September 2019.
Zhou N, Uzquiza AG, Zheng XY, Vogl D, Garfall AL, Bernabei L, Saraf A, Florens L, Washburn MP, Illendula A, Bushweller JH, Busino L: RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation. Leukemia 33(8): 2006-2021, August 2019.
Choi J, Saraf A, Florens L, Washburn MP, Busino L: PTPN14 regulates Roquin2 stability by tyrosine dephosphorylation. Cell Cycle 17(18): 2243–2255, September 2018.
Choi J, Lee K, Ingvarsdottir K, Bonasio R, Saraf A, Florens L, Washburn MP, Tadros S, Green MR, Busino L: Loss of KLHL6 promotes DLBCL growth and survival via stabilization of the mRNA decay factor Roquin2. Nature Cell Biology 20(5): 586-596, April 2018.
Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N: SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496(7443): 64-8, April 2013.
Busino L, Millman SE, Kyratsous C, Scotto L, Basrur V, Hoffmann A, O’Connor O, Elenitoba- Johnson K, Pagano M: SCFFbxw7-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma. Nature Cell Biology 14(4): 375-85, March 2012.
Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M: SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins. Science 316(5826): 900-4, May 2007.
Donzelli M, Busino L, Chiesa M, Ganoth D, Hershko A, Draetta GF: Hierarchical order of phosphorylation events commits Cdc25A to betaTrCP-dependent degradation. Cell Cycle 3(4): 469-71, April 2004.
Busino L, Chiesa M, Draetta GF, Donzelli M: Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 23(11): 2050-6, March 2004.
Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF: Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature 426(6962): 87-91, November 2003.
Lab Personnel
Sehbanul Islam
Mukul Mishra
Jiadong Tao
Monika Mittal
Karthik PrabakaranLesley Moreno, Administrative Assistant
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Read More about Lewis A. Chodosh, M.D., Ph.D.Lewis A. Chodosh, M.D., Ph.D.
Perelman Professor and Chair
Lewis A. Chodosh, M.D., Ph.D.
Perelman Professor and Chair
Associate Director for Basic Science, Abramson Cancer Center
Co-Director, 2-PREVENT Translational Center of Excellence
Investigator, Abramson Family Cancer Research InstituteContact Info
421 Curie Boulevard, 614 BRB II/III
Philadelphia PA, 19104-6160
T: (215) 898-1321 F: (215) 573-6725
chodosh@pennmedicine.upenn.edu
Education
B.S. (Molecular Biophysics & Biochemistry) Yale University, 1981
Ph.D. (Biochemistry) Massachusetts Institute of Technology, 1988
M.D. Harvard Medical School, 1989
Current Research
The Chodosh laboratory uses genetically engineered mouse models, patient samples and bioinformatics to understand the mechanisms by which cancers develop, progress to more aggressive states, and ultimately contribute to cancer mortality. A broad array of basic and translational research approaches are used to address problems of fundamental clinical importance to cancer patients by elucidating pathways and principles common to human cancers. These approaches encompass genetics, genomics, molecular biology, biochemistry, cell biology, computational biology, functional imaging, animal studies, preclinical trials and clinical investigation. Particular areas of interest include: pathways regulating cancer development, metastasis, tumor dormancy and recurrence; the use of genomics and computational approaches to understand genetic programs in cancer; the impact of obesity on cancer recurrence; the mechanisms by which pregnancy protects against breast cancer; and the use of non-invasive imaging approaches to study tumor biology.
Contact
Chodosh Laboratory
Department of Cancer Biology
421 Curie Boulevard, 627 BRB II/III
Philadelphia, PA 19104-6160
T: 215-898-0006 F: 215-573-6725Links
Contact Information
Jennifer McCallum - Lab Manager
Jennifer.McCallum@pennmedicine.upenn.edu
215-898-0275
Katelyn Carlin - Assistant Director, Administrative and Faculty Affairs
215-746-5031
Selected Publications
Eberle-Dwyer S, Ruth J, Seidel HE, Raz AA, and Chodosh LA. Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy. Breast Cancer Research, in press.
Agudo JA, Aguirre-Ghiso JA, Bhatia M, Chodosh LA, Correia AL, Klein CA. Viewpoint: Targeting cancer cell dormancy. Nature Reviews Cancer 24:97-104, 2024. doi: 10.1038/s41568-023-00642-x.
Lawrence-Paul MR, Pan TC, Pant DK, Shih NC, Chen Y, Belka GK, Feldman M, DeMichele A, and Chodosh LA. Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination. Genome Medicine 16(1):26, 2024. doi: 10.1186/s13073-024-01293-9.
Dalla E, Sreekumar A, Aguirre-Ghiso J and Chodosh LA. Dormancy in breast cancer. Cold Spring Harbor Perspectives in Medicine, 2023. doi: 19,1101/cshperspect.a041331.
Sreekumar A, Lu M, Choudhury B, Pan TC, Pant DK, Lawrence-Paul MR, Sterner CJ, Belka GK, Toriumi T, Benz B, Escobar-Aguirre E, Marino FE, Esko JD and Chodosh LA. B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling. Cancer Cell 42:52-69.e7, 2024. doi: 10.1016/j.ccell.2023.11.008.
Chen S, Paul MR, Sterner CJ, Belka GK, Wang D, Xu P, Sreekumar A, Pan TC, Pant DK, Makhlin I, DeMichele A, Mesaros C and Chodosh LA. PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies. Breast Cancer Research 25:1, 2023. doi:10.1186/s13058-022-01559-3.
Magbanua MJM, van 't Veer L, Clark AS, Chien AJ, Boughey JC, Han HS, Wallace A, Beckwith H, Liu MC, Yau C, Wileyto EP, Ordonez A, Solanki TI, Hsiao F, Lee JC, Basu A, Brown Swigart L, Perlmutter J, Delson AL, Bayne L, Deluca S, Yee SS, Carpenter EL, Esserman LJ, Park JW, Chodosh LA, and DeMichele A. Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study. Breast Cancer Research and Treatment 198:383-390, 2023.
Ruth JR, Pant DK, Pan TC, Seidel HE, Baksh SC, Keister BA, Singh R, Sterner CJ, Bakewell SJ, Moody SE, Belka GK and Chodosh LA. Cellular dormancy in minimal residual disease following targeted therapy. Breast Cancer Research23:63, 2021. doi: 10.1186/s13058-021-01416-9. PMCID PMC8178846
Paul MR, Pan TC, Pant DK, Shih NN, Chen Y, Harvey KL, Solomon A, Lieberman D, Morrissette JJD, Soucier-Ernst D, Goodman NG, Stavropoulos SW, Maxwell KN, Clark C, Belka GK, Feldman M, DeMichele A and Chodosh LA. Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets. Journal of Clinical Investigation 130(8):4252-4265, 2020. doi.org/10.1172/JCI129941. PMCID: PMC7410083
Ecker BL, Lee JY, Sterner CJ, Solomon AC, Pant DK, Shen F, Peraza J, Vaught L, Mahendra S, Belka GK, Pan TC, Schmitz KH, Chodosh LA. Impact of obesity on breast cancer recurrence and minimal residual disease. Breast Cancer Research, 21:41, 2019. PMCID: PMC6416940
Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ and Chodosh LA. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. Journal of Clinical Investigation 125:2484-2496, 2015.
Feng Y, Pan TC, Chakrabarti KR, Perez D, Pant D and Chodosh LA. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discovery 4:790-803, 2014.
Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou AY, Pant D, Grimley JS, Wandless TJ, DeMichele A, I-SPY 1 Trial Investigators and Chodosh LA. Par-4 down-regulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell, 24:30-44, 2013.
Yeh ES, Belka GK, Vernon AE, Chen CC, Jung JJ and Chodosh LA. Hunk negatively regulates c-myc to promote Akt-mediated cell survival and mammary tumorigenesis induced by loss of Pten. Proceedings of the National Academy of Sciences USA, 110:6103-6108, 2013.
Chen CC, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV and Chodosh LA. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes & Development, 26:2154-2168, 2012.
Yeh, ES, Yang TW, Jung JJ, Gardner HP, Cardiff RD and Chodosh LA. Hunk is required for HER2/neu-induced mammary tumorigenesis. Journal of Clinical Investigation, 121:866-879, 2011
Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE and Chodosh LA. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biology, 9:493-505, 2007.
Boxer RB, Stairs DB, Dugan KD, Notarfrancesco KL, Portacarrero CP, Keister BA, Belka GK, Cho H, Rathmell J, Thompson CB, Birnbaum MJ and Chodosh LA. Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation. Cell Metabolism, 4:475-490, 2006.
Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero C, Sterner CJ, Notorfrancesco K, Cardiff RD and Chodosh LA. The transcriptional repressor, Snail, promotes mammary tumor recurrence. Cancer Cell 8:197-209, 2005.
Boxer RB, Jang JW, Sintasath L and Chodosh LA. Lack of sustained regression of c–MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell, 6:577-586, 2004.
Gunther EJ, Moody SE, Belka GK, Hahn KT, Innocent N, Dugan KD, Cardiff RD and Chodosh LA. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes & Development, 17:488-501, 2003.
Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD, Innocent N, Cardiff RD, Schnall MD and Chodosh LA. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell, 2:451-461, 2002.
D’Cruz CM, Gunther EJ, Hartman J, Sintasath L, Moody SE, Boxer RB, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD and Chodosh LA. MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2mutations. Nature Medicine, 7:235-239, 2001.
Lab Personnel
Sarah Acolatse – Graduate Student
George Belka - Research Project Manager
Brian Benz - Graduate Student
Katelyn Carlin - Assistant Director, Administrative and Faculty Affairs kwichert@upenn.edu
Yan Chen - Research Specialist
Beth Chislock – Sr. Research Investigator
Jewell Graves - Research Specialist
Katherine Huang - Graduate Student
Morgan Kuczler – Graduate Student
Jennifer McCallum - Lab Manager Jennifer.McCallum@pennmedicine.upenn.edu
Heather Martin - Sr. Research Investigator
Nathan Mears - Lab Animal Technician
Tien-chi Pan – Staff Computational Biologist
Dhruv Pant – Staff Computational Biologist
Matt Paul – Postdoctoral Researcher
Ashvathi Raghavakaimal – Graduate Student
Emily Shea – Combined Degree (MD-PhD) Student
Amulya Sreekumar – Research Associate
Chris Sterner - Project Manager
Jianping Wang - Research Specialist
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Read More about David M. Feldser, Ph.D.David M. Feldser, Ph.D.
Associate Professor
David M. Feldser, Ph.D.
Associate Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 756 BRB II/III
Philadelphia PA, 19104-6160
T: 215-898-9203 F: 215-573-6725
Education
B.S. (Biochemistry and Molecular Biology) Juniata College, 1998
Ph.D. (Human Genetics and Molecular Biology) Johns Hopkins School of Medicine, 2007Links
Current Research
Our research is dedicated to deconstructing the multistep process of tumorigenesis. The major emphasis of our laboratory is to uncover the pathways that are disabled by mutational inactivation of tumor-suppressor genes as well as those pathways stimulated by aberrant oncogene activation. Areas of interest within the laboratory include: p53-regulated tumor immune surveillance, Rb-mediated tumor suppression, chemical genetic strategies to modulate tumor suppression, development of gene regulating tools for mouse models, and Kras signaling in lung cancer.
The Feldser Laboratory
The Feldser lab uses genetically engineered mouse models to study tumor progression and metastasis of common forms of human cancer. These models faithfully recapitulate many aspects of the histopathological progression of their human counterparts. Tumors initiate within the appropriate tissue microenvironment from single cells due to induced activation of latent oncogenes and/or deletion of key tumor suppressor genes. These lesions evolve through multiple cellular states toward malignant and metastatic disease. We focus on mouse models in order to employ novel genetic tools to regulate gene function at will in developing cancerous lesions as well as track cancer growth and dissemination via bioluminescent and fluorescent techniques. We couple cellular, genomic and biochemical analyses to our powerful in vivo tools to discern the mechanics of tumor progression and metastasis with the goal of identifying new therapeutic strategies to eradicate malignant cells.
Research interests
Cyclophilin-assisted programmed cell death
Genotype-dependent immune surveillance
Regulation of cell state plasticity
Cancer gene dependencies
Patents
D Feldser, TE Jacks, LM Schmidt: Methods and Products Related to Targeted Cancer Therapy. US Patent Number WO 2013116686 A1. 2012.
TE Jacks, W Xue, E Meylan, TG Oliver, D Feldser, M Winslow: Methods and Products Related to Lung Cancer. US Patent Number WO 2013185108 A1. 2013.Selected Publications
Metastatic competency and tumor spheroid formation are independent cell states governed by RB in lung adenocarcinoma
Nelson F. Freeburg, Nia Petersen, Dan A. Ruiz, Amy C. Gladstein, and David M. Feldser. Cancer Research Communications. Cancer Res Commun. 2023 Sep 20. doi: 10.1158/2767-9764.CRC-23-0172. Online ahead of print.PMID: 37728504
p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism
Jonuelle Acosta, Qinglan Li, Nelson F. Freeburg, Nivitha Murali, Grant P. Grothusen, Michelle Cicchini, Hung Mai, Amy C. Gladstein, Keren M. Adler, Katherine R. Doerig, Jinyang Li, Miguel Ruiz-Torres, Kimberly L. Manning, Ben Z. Stanger, Luca Busino, Liling Wan, David M. Feldser. Nature Communications. 2023 Jul 21;14(1):4403. doi: 10.1038/s41467-023-40161-9. PMID: 37479684
Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling
David M. Walter, Amy C. Gladstein, Katherine R. Doerig, Ramakrishnan Natesan, Saravana G. Baskaran, A. Andrea Gudiel, Keren M. Adler, Jonuelle O. Acosta, Douglas C. Wallace, Irfan A. Asangani, David M. Feldser. Communications Biology. 2023 Mar 10;6(1):255. doi: 10.1038/s42003-023-04618-3. PMID: 36899051
PKC epsilon is required for KRAS-driven lung tumorigenesis
Garg R, Cooke M, Benavides F, Abba MC, Cicchini M, Feldser DM, Kazanietz MG. Cancer Res. 2020 Sep 29:canres.1300.2020. doi: 10.1158/0008-5472.CAN-20-1300. Epub ahead of print. PMID: 32994205.
RB constrains lineage fidelity and multiple stages of tumour progression and metastasis
Walter DM, Yates TJ, Ruiz-Torres M, Kim-Kiselak C, Gudiel AA, Deshpande C, Wang WZ, Cicchini M, Stokes KL, Tobias JW, Buza E, Feldser DM. Nature. 2019 May;569(7756):423-427. doi: 10.1038/s41586-019-1172-9. Epub 2019 May 1. PMID: 31043741
Natural killer cells limit the clearance of senescent lung adenocarcinoma cells
Stokes, K, Acosta, J, Lauderback, B, Robles-Oteiza, C, Cicchini, M and Feldser, D.M. Oncogenesis. 2019 Apr 1;8(4):24. doi: 10.1038/s41389-019-0133-3. PMID: 30936429
Off and Back-On Again: A Tumor Suppressor’s Tale
Acosta J, Wang W, and Feldser DM (2018). Oncogene. 2018 Mar 15. doi: 10.1038/s41388-018-0186-3. [Epub ahead of print] Review. PMID: 29540833
Systematic in vivo inactivation of chromatin regulating enzymes identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma
Walter DM, Venancio OS, Buza EL, Tobias JW, Deshpande C, Gudiel AA, Kim-Kiselak C, Cicchini M, Yates TJ, and Feldser DM (2017). Cancer Research. 2017 Feb 15. pii: canres.2159.2016. doi: 10.1158/0008-5472.CAN-16-2159. [Epub ahead of print]. PMID: 28202515
Context dependent effects of amplified MAPK signaling during lung adenocarcinoma initiation and progression.
Cicchini M, Buza E.L., Sagal K.M., Gudiel A.A., Durham A.C., and Feldser DM (2017). Cell Reports. 2017 Cell Reports.2017 Feb 21;18(8):1958-1969. PMID: 28228261
XTR: A recombinase-based system for regulating gene function in a conditional and reversible manner
Robles-Oteiza C, Taylor SE, Yates T, Cicchini M, Lauderback B, Cashman C, Burds AA, Winslow M, Jacks T, Feldser DM (2015). Nature Communications. 2015 Nov 5;6:8783. PMID: 26537451
Stage-specific sensitivity to p53 restoration during lung cancer progression
Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, Sanchez-Rivera FJ, Resnick R, Bronson R, Hemann MT, Jacks T. Nature. 2010 Nov 25;468:572-5. PMID: 21107428; PubMed Central PMCID: PMC3003305.
Lab Personnel
Lesley Moreno, Administrative Assistant
Postdocs:
Trini Ochoa, Ph.D. University of Pennsylvania 2023
Maria Solares, Ph.D. Penn State University
Graduate Students:
Keren Adler, CB (2018)
Amy Gladstein, G&E (2019)
Katie Doerig, CB (2019)Research Specialist:
Maggie Robertson
Undergrad:
Faaiz Quaisar
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Read More about Roger A. Greenberg, M.D., Ph.D.Roger A. Greenberg, M.D., Ph.D.
J. Samuel Staub, M.D. Professor
Roger A. Greenberg, M.D., Ph.D.
J. Samuel Staub, M.D. Professor
Director of Basic Science, Basser Research Center for BRCA
Investigator, Abramson Family Cancer Research Institute
Director, Penn Center for Genome Integrity
Contact Info
421 Curie Boulevard, 513 BRB II/III
Philadelphia PA, 19104
T: (215) 746-2738 F: (215) 573-2486
rogergr@pennmedicine.upenn.edu
Education
B.A. (Chemistry) Haverford College, 1991
Ph.D. (Microbiology and Immunology) Albert Einstein College of Medicine, 2000
M.D. Albert Einstein College of Medicine, 2000
LinksCurrent Research
This laboratory is interested in identifying basic mechanisms involved in maintaining genome integrity and understanding their relationship to human malignancy. In particular, we are devoted to the elucidation of BRCA1-dependent signaling pathways necessary for appropriate repair of DNA double strand breaks and suppression of breast and ovarian cancer.
Key words: BRCA1, BRCA2, RAP80, BRCC36, MERIT40, Ubiquitin, ATM, DNA repair, chromatin, epigenetics, cellular senescence, Breast Cancer, Ovarian Cancer.Greenberg Lab
Germline mutation of either the Breast Cancer 1 (BRCA1) or Breast Cancer 2 (BRCA2) genes greatly predisposes individuals to breast and ovarian epithelial cancers. Clinical BRCA1 and BRCA2 mutations render cells deficient in DNA damage checkpoint signaling and error-free mechanisms of DNA repair known as homologous recombination, strongly supporting a role for these activities in tumor suppression.
Our research has contributed to the developing concept of a BRCA1-centered breast and ovarian tumor suppressor network. BRCA1 forms several distinct DNA damage inducible 'supercomplexes,' each dedicated to specific checkpoint and repair activities following genotoxic stress. These studies have provided a framework for understanding the in vivo consequences of mutations within the BRCA1 network (i.e. genes encoding BRCA1-interacting proteins) (Greenberg et al. Genes&Dev 2006). Recent work has revealed a partial molecular understanding for how BRCA1 recognizes DNA damage sites (Sobhian et al., Science 2007). We have demonstrated that an interaction between the BRCA1 BRCT domain and the RAP80 ubiquitin binding protein targets BRCA1 to K63-linked ubiquitin structures present at DNA damage sites. The RAP80 ubiquitin interaction motifs (UIMs) provide an ubiquitin recognition element to target the BRCA1 E3 ligase and a K63-ubiquitin specific deubiquitinating enzyme BRCC36 to DNA double strand breaks. Each of these activities is required for appropriate checkpoint and repair responses to ionizing radiation (Sobhian et al. Science 2007; Shao et al. Genes&Dev 2009; Shao et al. PNAS 2009; Nikkila et al. Oncogene 2009). Cancer causing BRCA1 BRCT mutants fail to interact with RAP80 and consequently demonstrate inefficient recruitment to DNA damage sites. Thus a series of ordered events involving ubiquitin recognition, breakdown and synthesis are required for BRCA1-dependent DNA damage responses. Future work will address the relationship between ubiquitin turnover and BRCA1-dependent DNA repair function. These studies should provide a detailed knowledge of the (1) molecular determinants required for BRCA1 recognition of DNA damage, and (2) how BRCA1 influences DNA repair mechanism specificity. Clinical mutations frequently disrupt these activities, thus understanding the basis for BRCA1 recognition of DNA damage should lend significant new insight into BRCA1 dependent DNA repair and tumor suppression mechanisms.
A second area of interest in the laboratory is the complex relationship between chromatin structure and DNA repair. We have recently developed novel systems to investigate interrelationships between chromatin structure and DNA double strand break (DSB) repair (Shanbhag et al. Cell 2010). Using these systems, we have shown that DSBs induce an ATM kinase dependent transcriptional silencing that spans multiple kilobases of chromatin in cis to the site of DNA damage. We intend to utilize these systems to reveal new insights into the interplay between chromatin structure and DNA repair, and how DNA repair responses influence diverse biological phenomena including cellular senescence and viral latency. We will also use these and related experimental systems to explore the molecular basis underlying epigenetic changes that occur during carcinogenesis.
Rotation projects are open to students in each of the areas the lab focuses on. Please see Roger Greenberg to discuss potential rotation projects.Selected Publications
01. Cho NW, Dilley RL, Lampson MA, Greenberg RA: Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis. Cell 159(1): 108-21, September 2014.
02. Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA: Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype. Cancer Discovery December 2014.
03. Tang J, Cho NW, Cui G, Manion EM, Shanbhag NM, Botuyan MV, Mer G, Greenberg RA: Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat Struct Mol Biol 20(3): 317-25, March 2013 Notes: Highlighted in Nature Reviews Mol Cell Biol 2013: Du Toit A. DNA damage: Limiting 53BP1.
04. Zheng H#, Gupta V#, Patterson-Fortin J#, Bhattacharya S#, Katlinski K, Wu J, Varghese B, Carbone CJ, Aressy B, Fuchs SY*, Greenberg RA*: A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses. Cell Rep. 2013 Oct 17;5(1):180-93. Notes: # co-first author * co-corresponding author.
05. Domchek SM*, Tang J, Jill Stopfer, Lilli DR, Tischkowitz M, Foulkes WD, Monteiro ANA, Messick TE, Powers J, Yonker A, Couch FJ, Goldgar D, Nathanson KL, Greenberg RA*: Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discovery 3(4): 399-405, April 2013 Notes: *co-corresponding authors. Highlighted in Cancer Discovery 2013: D’Andrea AD. BRCA1: A Missing Link in the Fanconi/BRCA Pathway.
06. Greenberg RA: BRCA1, everything but the RING? Science 334(6055): 459-60, 2012.
07. Solyom S, Aressy B, Pylkäs K, Patterson-Fortin J, Hartikainen JM, Kallioniemi A, Kauppila S, Nikkilä J, Kosma VM, Mannermaa A, Greenberg RA*, Winqvist R*: Recurrent breast cancer predisposition-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions of BRCA1. Science Trans Med 4(122): 122ra-23, 2012 Notes: *Denotes co-corresponding authorship.
08. Li ML and Greenberg RA: Links between genome integrity and BRCA1 tumor suppression. Trends in Biochem Sci 37(10): 418-24, 2012.
09. Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, and Greenberg RA: ATM dependent chromatin changes silence transcription in cis to DNA Double Strand Breaks. Cell 141: 970-81, June 2010 Notes: Comment in: ATM Creates a veil of transcriptional silence. Cell. 2010 Jun 11;141(6):924-6.
10. Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA: MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes & Development 23(6): 740-54, 2009 Notes: Comment in: Higher-order BRCA1 complexity Nature Reviews Molecular Cell Biology 10, 301-301 (May 2009); and in Cancer Biol Ther. 2009 Apr;8(7):571-2. Penn researchers identify new protein important in breast cancer gene's role in DNA repair.
Lab Personnel
Abigail Lemmon - Undergraduate Researcher
Anne Wondisford - Undergraduate Researcher
Jie Chen - Postdoctoral Researcher
Laura Murillo - Administative Coordinator murillo@upenn.edu
Lei Tian - Postdoctoral Researcher
Mischa Li - Graduate Student
Molly Brothers - Undergraduate Researcher
Priyanka Verma - Postdoctoral Researcher
Qinqin Jiang - Graduate Student
Robert Dilley - Graduate Student
Shane Harding - Postdoctoral Researcher
Tianpeng Zhang - Postdoctoral Researcher
Weihua Li - Research Specialist and Lab Manager
Xuejiao Yang - Postdoctoral Researcher
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Read More about Xianxin Hua, Ph.D.Xianxin Hua, Ph.D.
Professor
Xianxin Hua, Ph.D.
Professor
Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 412 BRB II/III
Philadelphia PA, 19104
T: (215) 746-5565 F: (215) 746-5525
Education
M.D. Hubei Medical College, 1983
M.S. (Medical Sciences) Hubei Medical College, 1986
Ph.D. (Cell Regulation) The University of Texas Southwestern Medical Center at Dallas, 1995
Links
Current Research
Our research focuses on elucidating the molecular mechanisms whereby menin-mediated epigenetic mechanisms in regulating endocrine cells including pancreatic beta cells, endocrine tumors, and MLL fusion protein-induced leukemia. In particular, we are interested in dissecting the function of menin, which is mutated in hereditary human tumor syndrome, Multiple Endocrine Neoplasia Type 1 (MEN1), in repressing beta cells and endocrine tumors and in promoting leukemogenesis.
1. We seek to elucidate how Menin suppresses endocrine cells, such as pancreatic beta cells, via regulating histone methylations and expression of pro-proliferative genes. We are also interested in identifying menin-regulated key pathways that can be suppressed to inhibit neuroendocrine tumors.
2. Determining how menin, which acts as a tumor promoter in MLL fusion protein-induced leukemia, cooperates with wild-type MLL protein to promote leukemia and how the menin and wt MLL axis can be suppressed to improve therapy for this aggressive leukemia.
3. Understanding how inhibition of menin leads to reversal of established diabetes in mouse models and determining whether the menin pathway could be explored to ameliorate diabetes.
4. Investigating the interplay between menin, post-transcriptional modifications of menin, and TGF-β signaling in repressing pancreatic beta cells. As both menin and TGF-β inhibit cell proliferation, we will test whether menin and TGF-β cooperate to suppress beta cell proliferation and the underlying mechanisms, using biochemical studies and mouse models.
These comprehensive approaches will provide novel insights into the molecular mechanisms for MEN1 tumorigenesis, regulation of beta cells, and leukemogenesis, shedding light on improving therapy against neuroendocrine tumors, leukemia, and diabetes.The Hua Laboratory
The research team of Xianxin Hua, Ph.D., seeks to understand how epigenetic regulations, especially those mediated by menin, control development of a variety of diseases, such as endocrine tumors, leukemia, and diabetes. His group has discovered that menin may act as a scaffold protein or a node to interact with various epigenetic regulators to control expression of genes that modulate cell proliferation and survival. They are elucidating how a cascade of the menin-mediated regulatory step is controlled at the molecular level, using a variety of approaches involving molecular and cell biology, genetics, and mouse models. They seek to help improve the treatment of the diseases by targeting the novel molecular steps.
Selected Publications
Xin He, Zijie Feng, Jian Ma, Yan Cao, Sunbin Ling, Xuyao Zhang, Bowen Xing, Bryson W Katona, Carl H June, Xianxin Hua.: CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody-switch. Leukemia March 2021.
Jian Ma1, Bowen Xing, Yan Cao, Xin He , Kate E Bennett, Chao Tong,Chiying An, Taylor Hojnacki, Zijie Feng, Sunbin Deng, Sunbin Ling, Gengchen Xie, Yuan Wu, Yue Ren, Ming Yu, Bryson W Katona, Hongzhe Li, Ali Naji, Xianxin Hua.: Menin-regulated Pbk controls High fat diet-induced compensatory beta cell proliferation. Embo Molecular Medicine 13(5), May 2021.
He X, Feng Z, Ma J, Ling S, Cao Y, Gurung B, Wu Y, Katona BW, O'Dwyer KP, Siegel DL, June CH, Hua X. : Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia. Blood 135(10): 713-723, March 2020.Matkar S, Sharma P, Gao S, Gurung B, Katona BW, Liao J, Muhammad AB, Kong XC, Wang L, Jin G, Dang CV, Hua X: An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis. Cancer Cell 28(4): 472-85, Oct 2015.
Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL: Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525(7568): 206-11, Sep 2015.
Matkar S, Katona BW, Hua X: Harnessing the Hidden Antitumor Power of the MLL-AF4 Oncogene to Fight Leukemia. Cancer Cell 25(4): 411-3, Apr 2014.
Matkar S, Thiel A, and Hua X: Menin: a scaffold protein that controls gene transcription and cell signaling. Trends in Biochemical Sciences (TIBS) 38(8): 394-402, Aug 2013.
Thiel AT, Feng Z, Pant DK, Chodosh LA and Hua X: The Trithorax Protein Partner Menin Acts in Tandem with EZH2 to Suppress C/EBPa and Differentiation in MLL-AF9 Leukemia. Haematologica 98(6): 918, Jun 2013.
Gurung B, Feng Z, Iwamoto DV, Thiel A, Jin G, Fan C-M, Ng JM, Curran T, Hua X: Menin Epigenetically Represses Hedgehog signaling in MEN1 Tumor Syndrome Cancer Research 73(8): 2650-8, Apr 2013.
Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X*, and Lei M* (*co-corresponding author) The same pocket in menin binds both MLL and JunD, but oppositely regulates transcription. Nature 432(7386): 542-6, 2012.
Lab Personnel
Brian Bakke - Research Specialist and Lab Manager
Buddha Gurung - Research Fellow
Xin He - Postdoctoral Researcher
Bryson Katona - Gastroenterology Fellow
Xiangchen Kong - Postdoctoral Researcher
Smita Matkar - Research Associate
Abdul Bari Muhammad - Postdoctoral Fellow
Kate Szigety - MD/PhD Graduate Rotation Student
Haoren Wang - Research Specialist
Lei Wang - Visiting Graduate Student
Heather Birmingham, Administrative Assistant
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Read More about Chengcheng Jin, Ph.D.Chengcheng Jin, Ph.D.
Assistant Professor
Chengcheng Jin, Ph.D.
Assistant Professor
Assistant Investigator Abramson Family Cancer Research Institute
Member, Institute for Immunology
Contact Info
421 Curie Boulevard, 706 BRB II/III
Philadelphia, PA 19104-6160
T: 215-746-1764; F: 215-573-6725
chengcheng.jin@pennmedicine.upenn.edu
Education
B.S. (Biological Science) Tsinghua University, 2007
Ph.D. (Cell Biology) Yale University, 2013
Links
Current Research
The pathogenesis of cancer involves not only intrinsic genetic alterations in tumor cells but also the failure of immune surveillance and unresolved inflammation. However, it is not well understood how host-intrinsic or environmental factors direct the immune response towards tumor-promoting inflammation versus anti-tumor immunity during tumor progression. In particular, mucosal surfaces exposed to the external environment are colonized by a vast number of microbes, collectively referred to as the commensal microbiota. Our work and the work of others have just begun to unveil the critical role of commensal microbiome in shaping the tumor microenvironment (TME) at the mucosal sites to regulate the tumor-immune interactions. This is as an area of tremendous opportunity for significant breakthroughs in cancer research.
The research at Jin lab lies at the forefront of: (1)Understanding how immune responses are initiated and evolve over time as tumors arise de novoand progress in the native TME; (2)Defining the molecular and cellular mechanisms by which the immune system senses and responds to microbiota-derived or tumor-intrinsic signals in the TME to regulate tumor growth and responses to therapies.
Jin Lab
We are combining multi-omics approaches, advanced imaging and mouse genetic models to address the fundamental questions in cancer immunology and mucosal immune-microbiota interaction. Findings from our research will not only advance our understanding of the fundamental immunobiology of tumorigenesis, but also provide critical insights into novel strategies for cancer prevention and treatment.
Specially, our research projects aim to
1. Elucidate the impacts of local and distal microbiota on tumor-associated immune responses in the lung.
Our current understanding about microbiota and cancer has been mostly limited to the intestinal microbiota. As a mucosal organ harboring the largest surface area in the body, the lung is exposed to a variety of air-borne microbes and also colonized by a diverse bacterial community in both physiological and pathological conditions. We have established various experimental tools to analyze and manipulate lung microbiota, and revealed their changes associated with tumor progression. Moving forward, we are working to further (1) elucidate the cellular and molecular components of the lung or intestinal microbiota that shape the TME in a spatial-temporal fashion; (2) understand how they orchestrate the balance between tumor-promoting inflammation and anti-tumor immunity to regulate tumor growth and response to therapies.
2. Reveal the spatial-temporal interactions between tumor and immune cells during cancer initiation and progression.
While intensive efforts in the field have been focused on tumor-immune interaction in established tumors, there is a critical gap in our knowledge about immune recognition and activation upon early oncogenic transformation, and about the co-evolution of immune cell populations with tumor cells during cancer progression. We have established genetically engineered mouse models that enable us to define the immune components of TME over the course of oncogenesis from nascently transformed cells to a full-blown tumor. Based on this system, we will take combinatorial approaches to perform a spatial-temporal analysis of tissue/tumor-infiltrating immune cells in regular and germ-free settings. Our goal is to understand the following long-standing questions in cancer immunology: (1) What types of immune cells interact with tumor cells at different stages of cancer development? (2) For a certain type of immune cells, do they function consistently from early to late stage, in the presence or absence of microbiota, or do they exhibit functional diversity and plasticity?
3. Define the host-intrinsic factors that shape the tumor immune microenvironment.
In addition to commensal microbiota, host-intrinsic factors are also critical in triggering immune recognition and activation in TME. While malignant transformation of epithelial cells leads to a dramatic change in their gene expression program over time and may thereby disrupt the normal immune-epithelial crosstalk, various damage or stress-associated molecules have also been implicated in the induction of innate immune response. Therefore, the goal of this project is to identify these host-intrinsic immuno-modulatory factors expressed from tumor cells or generated in the TME. We are integrating knowledge gained from the unbiased, genome-wide analysis of immune cells with the transcriptomic data of tumor cells at different time points of tumor development, and spearhead efforts in building signaling circuits and networks involved in epithelial-immune communication in a spatial-temporal fashion. Moreover, we will take advantage of the human cancer database to identify recurrent genetic alterations associated with human lung cancer, and examine how they influence tumor-immune interaction.
Altogether, we are broadly interested in understanding the mechanisms by which oncogene-driven molecular signatures, antigenic load, distinct tissue milieu and the local microbial compartment dictate the tumor-associated immune responses, and how we can target these mechanisms for more effective cancer therapies.
Selected Publications
1. Hu B*, Jin C*, Zeng X*, Resch JM, Jedrychowski MP, Yang Z, Banks AS, Lowell BB, Mathis D, Spiegelman BM. *Equal contribution.: γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578(7796): 610-614, Feburary 2020
2. Jin C, Lagoudas G, Zhao C, Bullman S, Bhutkar A, Hu B, Mazzilli S, Ameh S, Sandel D, Liang X, Whary M, Meyerson M, Germain R, Blainey P, Fox J, Jacks T. (2019) Commensal microbiota promote lung cancer development via γδ T cells. Cell.176: 1–16
3. Hu B*, Jin C*, Li HB*, Tong J, Ouyang X, Zhu S, Strowig T, Lam FC, Zhao C, Henao-Mejia J, Fitzgerald KA, Eisenbarth SC, Elinav E, Flavell RA. (2016) The DNA sensing Aim2 inflammasome controls radiation induced cell death and tissue injury. Science.354(6313):765-768.*Equal contribution.
4. Henao-Mejia J*, Elinav E*, Jin C*, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 482(7384): 179-85. *Equal contribution.
5. Jin C, Frayssinet P, Pelker R, Cwirka D, Hu B, Vignery A, Eisenbarth SC, Flavell RA. (2011) NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proceedings of the National Academy of Sciences USA (PNAS). 108(36): 14867-72.
6. Li HB*, Jin C*,Chen Y, Flavell RA. (2014) Inflammasome activation and metabolic disease progression. Cytokine & Growth Factor Reviews.25(6): 699-706. Review. *Equal contribution.
7. Elinav E*, Nowarski R*, Thaiss C*, Hu B*, Jin C*, Flavell RA. (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nature Reviews Cancer. 13(11): 759-71. Review. *Equal contribution.
8. Jin C, Flavell RA. (2013) Innate sensors of pathogen and stress: linking inflammation to obesity. Journal of Allergy and Clinical Immunology. 132(2): 287-94. Review
9. Jin C, Henao-Mejia J, Flavell RA. (2013) Innate immune receptors: key regulators of metabolic diseases progression. Cell Metabolism.17(6): 873-82. Review
10. Jin C, Flavell RA. (2010) Molecular mechanism of NLRP3 inflammasome activation. Journal of Clinical Immunology. 30(5): 628-31. Review.
11. Jin C, Flavell RA. (2010) Inflammasome activation. The missing link: how the inflammasome senses oxidative stress. Immunol Cell Biol. 88(5): 510-2
12. Hu B,Elinav E, Huber S, Strowig T, Hao L, Hafemann A, Jin C, Eisenbarth SC, Flavell RA. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. (2013) Proceedings of the National Academy of Sciences USA (PNAS). 110(24): 9862-9867.
13. Hu B,Elinav E, Huber S, Booth CJ, Strowig T, Jin C, Eisenbarth SC, Flavell RA. (2010) Inflammation- induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proceedings of the National Academy of Sciences USA (PNAS). 107(50): 21635-40.
Lab Personnel
Eric Chen - Research Specialist
Qing Dong - Postdoctoral Fellow
Zachary Stotz - Undergraduate Researcher
Haohan (Karen) Wei - Graduate Student Rotation
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Read More about Junwei Shi, Ph.D.Junwei Shi, Ph.D.
Associate Professor
Junwei Shi, Ph.D.
Associate Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 610 BRB II/III
Philadelphia , 19104-6160
T: 215-746-5733 F: 215-573-6725
Education
B.S. (Biotechnology) Sun Yat-sen University, 2008
Ph.D. (Molecular and Cellular Biology) Stony Brook University, SUNY, 2016
Links
Current Research
The physiological effects of cancer are a manifestation of the genetic abnormalities that cause the disease. While much progress has been made in the understanding of such genetic perturbations, scientists still struggle to effectively identify, understand, and treat cancer-causing mutations. This is due to the fast-paced evolution of the disease, and the accumulation of novel mutations that permit cell survival even in the harsh environment created by a therapeutic. CRISPR is a gene-editing technology that couples the elegance of base complementarity with the enzymatic activity of a DNA nuclease in order to introduce mutations into target loci. CRISPR technologies help advance our understanding of the genetic perturbations that contribute to cancer maintenance.
Current areas of interest within the lab include: (1) Defining the functional importance of epigenetic regulators in leukemia, (2) Development and optimization of AsCas12a for multiplex genetic dropout screening, and (3) Developing new functional genomic tools.
Research Details
While whole exome sequencing of the leukemia cancer genome revealed many oncogene mutations, few of these genetic alterations lead to directly actionable therapeutic opportunities. A major objective of the lab is to annotate and dissect these genetic vulnerabilities in leukemia. To approach this, we use our highly developed domain-focused CRISPR genetic knockout screening technology, where CRISPR-mediated mutagenesis is directed to gene sequences encoding critical protein domains. This method generates a larger fraction of functional null-alleles, which increase the severity in a negative selection-based genetic screen. In contrast to RNA interference-based methods or prior CRISPR-based screening approaches, this new method is not only more efficient than other screening approaches, but also has the potential to evaluate protein domain function directly from genetic screening, and may allow high-throughput identification of protein domains that are suitable drug targets in cancer. Coupling functional genomics screening, biochemical assays, and pre-clinical mouse models, we investigate the aberrant transcription signaling networks of leukemia and explore them as potential therapeutic opportunities. Since genetic screenings are only as successful as the underlying technology, a major focus of the lab is to further optimize and expand our screening toolbox. Projects are underway to engineer different Cas proteins for multiplex genetic screening using a variety of methods, including structure-guided rational design and directed evolution. Our ultimate goal is to uncover complex genetic interactions in leukemia that are therapeutically tractable.
Just Published
Gier, R.A., Budinich, K.A., Evitt, N.H., Cao, Z., Freilich, E., Chen, Q., Qi, J., Lan, Y., Kohli, R., and Shi, J*. High-performance CRISPR-Cas12a genome editing for combinatorial genetic screening. Nat Commun 11, 3455, 2020.
Selected Publications
01. Johannes Zuber*, Junwei Shi*, Eric Wang, Amy R. Rappaport, Harald Herrmann, Edward A. Sison, Daniel Magoon, Jun Qi, Katharina Blatt, Mark Wunderlich, Meredith J. Taylor, Christopher Johns, Agustin Chicas, James C. Mulloy, Scott C. Kogan, Patrick Brown, Peter Valent, James E. Bradner, Scott W. Lowe and Christopher R. Vakoc. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478(7370): 524-528, 2011. Notes: *These authors contributed equally to this work.
02. Jake E. Delmore, Ghayas C. Issa, Madeleine E. Lemieux, Peter B. Rahl, Junwei Shi, Hannah M. Jacobs, Efstathios Kastritis, Timothy Gilpatrick, Ronald M. Paranal, Jun Qi, Marta Chesi, Anna C. Schinzel, Michael R. McKeown, Timothy P. Heffernan, Christopher R. Vakoc, P. Leif Bergsagel, Irene M. Ghobrial, Paul G. Richardson, Richard A. Young, William C. Hahn, Kenneth C. Anderson, Andrew L. Kung, James E. Bradner and Constantine S. Mitsiades. BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell 146(6): 904-917, 2011.
03. Junwei Shi, Warren A. Whyte, Cinthya Zepeda-Mendoza, Joseph Milazzo, Chen Shen, Jae S. Roe, Jessica Minder, Fatih Mercan, Eric Wang, Melanie A. Eckersley-Maslin, Amy E. Campbell, Shinpei Kawaoka, Sarah Shareef, Zhu Zhu, Jude Kendall, Matthias Muhar, Christian Haslinger, Ming Yu, Robert G. Roeder, Michael A. Wigler, Gerd A. Blobel, Johannes Zuber, David L. Spector, Richard A. Young, and Christopher R. Vakoc Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation Genes and Development 27(24): 2648-2662, 2013.
04. Junwei Shi, Eric Wang, Joseph P. Milazzo, Zhihua Wang, Justin B Kinney, Christopher R. Vakoc. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nature Biotechnology 33(6): 661-667, 2015.
05. Jonathan J. Ipsaro, Chen Shen, Eri Arai, Yali Xu, Justin B. Kinney, Leemor Joshua-Tor, Christopher R. Vakoc*, and Junwei Shi* Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesis. PLoS One: 12(2):e0172177, 2017 Feb 23 *co-corresponding author
06. Isaia Barbieri, Konstantinos Tzelepis, Luca Pandolfini, Junwei Shi, Gonzalo Millán-Zambrano, Samuel C Robson, Demetrios Aspris, Valentina Migliori, Andrew J Bannister, Namshik Han, Etienne De Braekeleer, Hannes Ponstingl, Alan Hendrick, Christopher R Vakoc, George S Vassiliou, and Tony Kouzarides Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017 Dec 7;552(7683):126-131.
07. Vivek Behera, Perry Evans, Carolyne J Face, Nicole Hamagami, Laavanya Sankaranarayanan, Cheryl A Keller, Belinda Giardine, Kai Tan, Ross C Hardison, Junwei Shi, and Gerd A Blobel. Exploiting genetic variation to uncover rules of transcription factor binding and chromatin accessibility. Nature Communication. 2018 Feb 22;9(1):782
08. Yusuke Tarumoto, Bin Lu, Tim D. D. Somerville, Yu-Han Huang, Joseph P. Milazzo, Xiaoli S. Wu, Olaf Klingbeil, Osama E. Demerdash, Junwei Shi#, and Christopher R. Vakoc# LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia. Molecular Cell. 2018 Mar 15;69(6):1017-1027 * co-corresponding author
09. Yu-Han Huang, Xiaoli Wu, Olaf Klingbeil, Xue-Yan He, Gayatri Arun, Bin Lu, Tim D. D. Somerville, Joseph P. Milazzo, John E. Wilkinson, Osama E. Demerdash, David L. Spector, Mikala Egeblad, Junwei Shi, and Christopher R. Vakoc. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes and Development. 2018 Jul 1;32(13-14):915-928
10.Maria Paz Zafra, Emma M Schatoff, Alyna Katti, Miguel Foronda, Marco Breinig, Anabel Y Schweitzer, Amber Simon, Teng Han, Sukanya Goswami, Emma Montgomery, Jordana Thibado, Edward R Kastenhuber, Francisco J Sánchez-Rivera, Junwei Shi, Christopher R Vakoc, Scott W Lowe, Darjus F Tschaharganeh, and Lukas E Dow. Optimized base editors enable efficient editing in cells, organoids and mice. Nature Biotechnology. 2018 Jul 3
11. Jeremy D Grevet, Xianjiang Lan, Nicole Hamagami, Christopher R Edwards, Laavanya Sankaranarayanan, Xinjun Ji, Saurabh K Bhardwaj, Carolyne J Face, David F Posocco, Osheiza Abdulmalik, Cheryl A Keller, Belinda Giardine, Simone Sidoli, Ben A Garcia, Stella T Chou, Stephen A Liebhaber, Ross C Hardison, Junwei Shi#, and Gerd A Blobel# Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science. 2018 Jul 20;361(6399):285-290 # co-corresponding author
12.Gerard L. Brien, David Remillard, Junwei Shi, Matthew L. Hemming, Jonathon Chabon, Kieran Wynne, Eugène T. Dillon, Gerard Cagney, Guido Van Mierlo, Marijke P Baltissen, Michiel Vermeulen, Jun Qi, Stefan Fröhling, Nathanael S. Gray, James E. Bradner, Christopher R. Vakoc and Scott A. Armstrong Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma Elife. 2018 Nov 15;7. pii: e41305. PMID: 30431433
13.Bin Lu, Olaf Klingbeil, Yusuke Tarumoto, Tim D. D. Somerville, Yu-Han Huang, Yiliang Wei, Dorothy C. Wai, Jason K.K. Low, Joseph P. Milazzo, Xiaoli S. Wu, Zhendong Cao, Xiaomei Yan, Osama E. Demerdash, Gang Huang, Joel P. Mackay, Justin B. Kinney, Junwei Shi#, and Christopher R. Vakoc# (# co-corresponding author) A transcription factor addiction in leukemia imposed by the MLL promoter sequence Cancer Cell. 2018 Dec 10;34(6):970-981 PMID: 30503706
14.Bell, C.C., Fennell, K.A., Chan, Y.C., Rambow, F., Yeung, M.M., Vassiliadis, D., Lara, L., Yeh, P., Martelotto, L.G., Rogiers, A., Kremer, B.E., Barbash, O., Mohammad, H.P., Johanson, T.M., Burr, M.L., Dhar, A., Karpinich, N., Tian, L., Tyler, D.S., MacPherson, L., Shi, J., Pinnawala, N., Yew Fong, C., Papenfuss, A.T., Grimmond, S.M., Dawson, S.J., Allan, R.S., Kruger, R.G., Vakoc, C.R., Goode, D.L., Naik, S.H., Gilan, O., Lam, E.Y.N., Marine, J.C., Prinjha, R.K., Dawson, M.A. Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nature Communications 10(1):2723.
15.Chan, K., Robert, F., Oertlin, C., Kapeller-Libermann, D., Avizonis, D., Gutierrez, J., Handly-Santana, A., Doubrovin, M., Park, J., Schoepfer, C., Da Silva, B., Yao, M., Gorton, F., Shi, J., Thomas, C.J., Brown, L.E., Porco, J.A. Jr, Pollack, M., Larsson, O., Pelletier, J., Chio, I.I.C. eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Nature Communications 10(1):5151. doi: 10.1038/s41467-019-13086-5.
16.Chen Z, Arai E, Khan O, Zhang Z, Ngiow SF, He Y, Huang H, Manne S, Cao Z, Baxter AE, Cai Z, Freilich E, Ali MA, Giles JR, Wu JE, Greenplate AR, Kurachi M, Nzingha K, Ekshyyan V, Wen Z, Speck NA, Battle A, Berger SL, Wherry JE*, Shi J*. In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer. BioRxiv, 2020 preprint link: https://www.biorxiv.org/content/10.1101/2020.05.20.087379v1 (*co-corresponding author)
17.Huang P, Peslak SA, Lan X, Khandros E, Yano JA, Sharma M, Keller CA, Giardine B, Qin K, Abdulmalik O, Hardison RC, Shi J*, Blobel GA*. The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood. 2020 Jun 11;135(24):2121-2132. doi: 10.1182/blood.2020005301. PubMed PMID: 32299090; PubMed Central PMCID: PMC7290097.(*co-corresponding author)
18.Yuan S, Natesan R, Sanchez-Rivera FJ, Li J, Bhanu NV, Yamazoe T, Lin JH, Merrell AJ, Sela Y, Thomas SK, Jiang Y, Plesset JB, Miller EM, Shi J, Garcia BA, Lowe SW, Asangani IA, Stanger BZ. Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression. Cancer Discov. 2020 Jun;10(6):854-871. doi: 10.1158/2159-8290.CD-19-1299. Epub 2020 Mar 18. PubMed PMID: 32188706; PubMed Central PMCID: PMC7269857.
Lab Personnel
Roopsha Bandopadhyay, Ph.D. Student
Yuqiao Liu, Research Specialist
Bianca Pingul, Ph.D. Student
Diqiu Ren, Postdoctoral Researcher
Deb Sneddon - Program Coordinator dsneddon@upenn.edu
Ping Wang - Postdoctoral Researcher
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Read More about Dana Silverbush, Ph.D.Dana Silverbush, Ph.D.
Assistant Professor
Dana Silverbush, Ph.D.
Assistant Professor
Contact Info
421 Curie Blvd, 509 BRB II/III
Philadelphia, PA 19104-6160
dana.silverbush@pennmedicine.upenn.edu
The Silverbush Lab
Tumors are complex and heterogeneous systems, which challenge their classification and treatment. The Silverbush lab decodes tumor heterogeneity and plasticity to understand how cancer cells transform to become more aggressive or evade treatment. We particularly examine hard-to-treat cancers with high heterogeneity, focusing on the notorious kings of heterogeneity and aggressiveness: brain cancers.
To achieve this goal, we develop and implement multi-omic single-cell tools. These tools enable us, for the first time, to simultaneously measure DNA methylation, point mutations, and transcriptional activity in the same single cells. To tackle these complex goals, we build an interdisciplinary team, welcoming MDs, biologists, immunologists, computational biologists, and pure computer scientists focusing on ML and AI. The lab encompasses wet lab and computational components, managing complex algorithmic and wet lab challenges, translational applications, and working closely with clinicians.
On-going and future projects (including rotation opportunities):
Deciphering Tumor Evolution Using Multi-omic Single Cells: Tumors are complex systems, heterogeneous on multiple levels. We can observe their patterns of heterogeneity at the transcriptomic, genetic, and epigenetic levels. However, we lack an understanding of how these levels work in conjunction or how they contribute to treatment resistance. In this project, we measure point mutations and the transcriptome from the same single cell, using the newest technique we developed, and analyze the data to uncover various layers of heterogeneity and establish connections between them.
Explore Clinical Trials through the Lens of Tumor Heterogeneity: For decades, teams have attempted to discover effective treatments for GBM and have tested therapeutics within the framework of clinical trials. Currently, no GBM clinical trial has demonstrated substantial improvement. The hypothesis is that these treatments may be effective only on a subset of patients or a subset of cells, depending on their tumor composition. In this effort, we build both experimental techniques and computational ML solutions to examine the changes in tumor and microenvironment through treatment. Specifically, we are investigating the alterations in tumor composition and the infiltration of T cells following the novel cutting-edge CART T cell therapy.
ML Solutions for Accurate Diagnosis and Prognosis: A key obstacle in cancer treatment is administering the right drug at the right time, before the target becomes obsolete. This has proven crucial in IDH mutant glioma, with the first-ever IDH mutant glioma successful clinical trials to treat these tumors showing efficacy when given early enough to patients. What is early enough? This is still largely unknown, as these tumors progress and change their composition in yet-to-be-discovered patterns. In the project, we design and implement novel ML solutions to identify the pattern of multi-omic longitudinal changes in patient samples. This approach aims to first decipher the evolution of these tumors and second, provide an actionable tool used by our collaborators around the world to obtain an accurate diagnosis and pinpoint the correct point of therapeutic intervention.
For further reading, please check out:
- Multi omic single cell studies to decipher tumor heterogeneity and plasticity: Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states
- Computational biology to correct tumor classification and prognosis: Predict tumor composition from bulk DNA methylation profile
Lab Personnel
Nelson (Trip) Freeburg - Postdoc
- Multi omic single cell studies to decipher tumor heterogeneity and plasticity: Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states
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Read More about Liling Wan, Ph.D.Liling Wan, Ph.D.
Assistant Professor
Liling Wan, Ph.D.
Assistant Professor
Assistant Investigator, Abramson Family Cancer Research Institute
Core Member, Penn Epigenetics Institute
Member, Institute for Regenerative Medicine
Contact Info
421 Curie Blvd, 751 BRB II/III
Philadelphia, PA 19104-6160
F: 215-573-6725
liling.wan@pennmedicine.upenn.edu
Education
B.S. (Biological Sciences and Biotechnology), Tsinghua University, 2008
Ph.D. (Molecular Biology), Princeton University, 2014
Links
Keywords:
cancer, epigenetics, genome organization, histone modifications, transcriptional condensates, cell fate plasticity, Leukemia, Kidney development, metastasis.
Research Details:
Chromatin - the complex of DNA and histone proteins - is the physiological template of the eukaryotic genome through which transcription factors, signaling pathways, and other internal and external cues alter gene activity and cellular phenotypes. Cancer genome studies have shown that at least 40% of human cancers harbor mutations in genes encoding chromatin-associated factors, highlighting the widespread impact of chromatin misregulation in cancer. Our research focuses on understanding chromatin function and its dysregulation in human cancer, particularly in exploring how these mechanisms regulate cellular fate transitions and plasticity that promote tumorigenic potential. In addition to our basic mechanistic discoveries, we are also committed to leveraging this knowledge for therapeutic development.Our lab currently pursues several key areas of research: (1) Investigating the molecular basis and functional consequences of cancer-associated mutations in chromatin regulators; (2) Decoding the regulation and function of chromatin-associated transcriptional condensates; (3) Examining how epigenomic reprogramming influences transcriptional and cellular plasticity to affect cancer behaviors such as metastasis; and (4) Characterizing drugs targeting newly identified epigenetic mechanisms in cancer.
Research Techniques:
We use a host of different approaches including mouse models of disease, genome-wide sequencing, advanced imaging, functional genomics, and biochemistry.
Rotation Projects:
Rotation projects are available in each area of interest in the lab. Please contact Dr. Wan for details.Selected Publications:
Liu Y*, Li Q*, Song L, Gong C, Tang S, Budinich KA, Vanderbeck A, Mathias KM, Wertheim GB, Nguyen SC, Outen R, Joyce EF, Maillard I, Wan L# . Condensate-promoting ENL mutation drives tumorigenesis in vivo through dynamic regulation of histone modifications and gene expression. Cancer Discovery 2024 Aug 2;14(8):1522-1546. doi: 10.1158/2159-8290.CD-23-0876. PMID: 38655899
Song L*, Li Q*, Xia L, Sahay A, Qiu Q, Li Y, Li H, Sasaki K, Susztak K, Wu H, Wan L#. Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape. Nature Communications 2024 Jul 15;15(1):5937. doi: 10.1038/s41467-024-50171-w. PMID: 3900956
Mathias KM*, Liu Y*, Wan L#. Dysregulation of transcriptional condensates in human disease: mechanisms, biological functions, and open questions. Current Opinion in Genetics & Development 2024 Jun:86:102203. doi: 10.1016/j.gde.2024.102203. Epub 2024 May 23. PMID: 38788489
Michino M*, Khan TA*, Miller MW, Fukase Y, Vendome J, Adura C, Glickman JF, Liu Y, Wan L, Allis CD, Stamford AW, Meinke PT, Renzetti LM, Kargman S, Liverton NJ, Huggins DJ. Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055. ACS Med. Chem. Lett. 2024,15, 4, 524–532, PMID: 38628784
Acosta J, Li Q, Freeburg N, Murali N, Indeglia A, Grothusen G, Cicchini M, Mai H, Gladstein A, Adler K, Doerig K, Li J, Ruiz-Torres M, Manning K, Stanger B, Busino L, Murphy M, Wan L, Feldser D. p53 restoration in small cell lung cancer identifies a latent Cyclophilin-dependent necrosis mechanism. Nature Communications. 2023 Jul 21;14(1):4403. PMID: 37479684
Zhou N, Choi J, Grothusen G, Kim BJ , Ren D, Cao Z, Beer T, Tang HY, Perkey E, Maillard I, Bonasio R, Shi J, Liu Y, Li Q, Inamdar A, Ruella M, Wan L, Busino L. DLBCL associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemo-resistance. Blood 2023 Sep 14;142(11):973-988. PMID: 37235754
Wang X*, Fan D*, Han Q*, Liu Y*, Miao H, Wang X, Li Q, Chen D, Gore H, Himadewi P, Pfeifer GP, Cierpicki T, Grembecka J, Su J, Chong S#, Wan L#, Zhang X#. Mutant NPM1 hijacks transcriptional hub to maintain pathogenic gene programs in acute myeloid leukemia. Cancer Discovery 2023 Mar 1;13(3):724-745. PMC9975662
Song L*, Yao X*, Li H, Peng B, Boka AP, Liu Y, Chen G, Liu Z, Mathias KM, Xia L, Li Q, Mir M, Li Y#, Li H#, Wan L#.Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer. Molecular Cell, 2022 Nov 3;82(21):4080-4098.e12. (featured in cover) PMC10071517
Liu Y, Li H, Alikarami F, Barrett DR, Khan TA, Michino M, Hill C, Mahdavi L, Song L, Tang S, Yang L, Li Y, Pokharel SP, Li Q, Stamford AW, Liverton N, Renzetti LM, Taylor S, Watt GF, Ladduwahetty T, Kargman S, Meinke PT, Foley MA, Shi J, Li H, Chen CW, Gardini A, Huggins DJ, Bernt KM#, Wan L#. Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia. Cancer Discovery. 2022 Nov 2;12(11):2684-2709. PMID: 36053276
Shen, M, Smith, H.A, Wei, Y., Jiang Y, Zhao S, Wang N, Rowicki M, Tang Y, Hang X, Wu S., Wan L, Shao Z., Kang Y. Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer. Nature Cancer 2022 Jan;3(1):60-74. PMC8818088
Wan L#, Chong S, Fan X, Liang A, Cui X, Gates L, Carroll TS, Li Y, Feng L, Chen G, Wang S, Ortiz MV, Daley S, Wang X, Xuan H, Kentsis A, Muir TW, Roeder RG, Li H, Li W, Tjian R, Wen H#, Allis CD#. Impaired Cell Fate through Gain-of-function Mutations in a Chromatin Reader. Nature 2020 Jan; 577(7788):121-126 (#co-corresponding) PMC7061414
Wan L*, Wen H*, Li Y*, Lyu J, Xi Y, Hoshii T, Joseph JK, Wang X, Loh YE, Erb MA, Souza AL, Bradner JE, Shen L, Li W, Li H#, Allis CD#, Armstrong SA#, Shi X#. ENL Links Histone Acetylation to Oncogenic Gene Activation in Leukemias. Nature 2017 Mar 9;543(7644):265-269. PMID: 28241141
Wan L, Lu X, Yuan S, Wei Y, Guo F, Shen M, Yuan M, Chakrabarti R, Hua Y, Smith HA, Blanco MA, Chekmareva M, Wu H, Bronson RT, Haffty BG, Xing Y, Kang Y. MTDH-SND1 Interaction Is Crucial for Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors. Cancer Cell 2014 Jul 14;26(1):92-105. PMC4101059
Guo F*, Wan L*, Zheng A, Stanevich V, Wei Y, Satyshur KA, Shen M, Lee W, Kang Y#, Xing Y#. Structural Insights into the Tumor-Promoting Function of the MTDH-SND1 Complex. Cell Reports 2014 Sep 25;8(6):1704-13. (*co-first;#co-senior). PMC4309369
Wan L, Hu G, Wei Y, Yuan M, Bronson RT, Yang Q, Siddiqui J, Pienta KJ, Kang Y. Genetic Ablation of Metadherin Inhibits Autochthonous Prostate Cancer Progression and Metastasis. Cancer Research 2014 Sep 15;74(18):5336-47. PMC4167565
Wan L, Pantel K, Kang Y. Tumor Metastasis: Moving New Biological Insights into the Clinic. Nature Medicine 2013 Nov;19(11):1450-64. PMID: 24202397
Lab Personnel
Lele Song - Postdoctoral Researcher
Yiman Liu - Postdoctoral Researcher
Qinglan Li - Postdoctoral Researcher
Krista Budinich - Graduate Student
Kaeli Mathais - Graduate Student
Chujie Gong - Graduate Student
Arushi Sahay -Graduate Student
Katherine Dong – Master Student
Michelle Lee - Undergraduate Student
Heather Birmingham, Administrative Assistant
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Read More about Kathryn E. Wellen, Ph.D.Kathryn E. Wellen, Ph.D.
Professor and Vice Chair
Kathryn E. Wellen, Ph.D.
Professor and Vice Chair
Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 653 BRB II/III
Philadelphia PA, 19104-6160
T: (215) 746-8599 F: 215-573-6725
Education
B.S. (Biological Psychology, summa cum laude) The College of William and Mary, 2000
Ph.D. (Division of Biological Science & Department of Genetics and Complex Diseases) Harvard University, School of Public Health, 2006
Links
Current Research
Cells rely on accurate assessment of nutrient availability in order to make decisions about growth and proliferation, differentiation and function, and even their own survival. Our laboratory’s research aims to elucidate mechanisms of crosstalk between metabolic pathways, signaling networks, and the epigenome. We have a major focus acetyl-CoA metabolism, which plays crucial roles at this intersection, due to its dual roles in both lipid synthesis and as the acetyl donor for acetylation reactions. Current projects in the lab are investigating mechanisms through which metabolites are sensed and the cellular processes regulated by metabolite sensing mechanisms, the role of nutrition in regulating acetyl-CoA metabolism in different cell types and how this impacts systemic metabolic health, and how acetyl-CoA production and utilization is altered in cancer cells, exposing potential therapeutic vulnerabilities.
Wellen Lab
Growth factor signaling directs nutrient uptake and metabolism, and reciprocally, intracellular metabolite levels influence signaling and gene expression. Many critical signaling molecules and transcription factors are subject to modifications, such as acetylation and glycosylation, that are metabolically sensitive and may be altered in cancer cells.
We have recently demonstrated that acetylation of histones, and associated changes in gene expression, are responsive to glucose availability in a manner dependent on ATP-citrate lyase (ACL), a metabolic enzyme that cleaves mitochondria-derived citrate to produce acetyl-CoA in the nucleus and cytoplasm. Hence, histones can be modified in a manner responsive to nutrient availability, potentially influencing multiple chromatin-dependent processes. A major current focus of the lab is to elucidate the mechanisms through which ACL regulates acetylation and its impact on signaling and gene expression, using cancer and metabolic cell types and mouse models.
A second area of interest is in understanding the role of the hexosamine biosynthetic pathway in regulating metabolism and growth. The hexosamine pathway is a branch of glucose metabolism that produces UDP-N-acetylglucosamine (UDP-GlcNAc), a donor substrate used in the production of several types of glycans, including N-linked glycans. Many cell surface and secreted proteins are modified co-translationally by N-linked glycosylation, and these glycoproteins can be influenced by metabolic state through glucose flux into the hexosamine pathway. Changes in the function and surface expression of glycoproteins can impact tumor growth by altering cancer cells’ interactions with their environment, including their ability to respond to growth factors and acquire nutrients. We are currently investigating how the hexosamine biosynthetic pathway is regulated in cancer cells and its impact on cancer cell growth and proliferation.Selected Publications
01. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, and Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009 May 22; 324(5930):1076-80.
02. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S, Jackson E, Aiello NM, Haas NB, Rebbeck T, Judkins A, Won KJ, Chodosh LA, Garcia BA, Stanger BZ, Feldman MD, Blair IA, and Wellen KE. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation, Cell Metab; 2014 Aug 5;20(2):306-19.
03. Zhao S, Torres AM, Henry R, Trefely T, Wallace M, Lee JV, Carrer A, Sengupta A, Kuo YM, Frey AJ, Meurs N, Viola JM, Blair IA, Weljie A, Snyder NW, Andrews AJ, Wellen KE. ATP-citrate lyase controls a glucose-to-acetate metabolic switch, Cell Rep, 2016 Oct 18;17(4):1037-1052.
04. Carrer A, Parris JLD, Trefely S, Henry RA, Montgomery DC, Torres A, Viola JM, Kuo YM, Blair IA, Meier JL, Andrews AJ, Snyder NW, Wellen KE. Impact of high fat diet on tissue acyl-CoA and histone acetylation levels, J Biol Chem, 2017 Feb 24; 292(8):3312-3322.
05. Sivanand S, Rhoades S, Jiang Q, Lee JV, Benci J, Zhang J, Yuan S, Viney I, Zhao S, Carrer A, Bennett MJ, Minn AJ, Weljie AM, Greenberg RA, Wellen KE. Nuclear acetyl-CoA production by ACLY promotes homologous recombination, Mol Cell, 2017 Jul 20;67(2):252-265.
06. Sivanand S, Viney I, Wellen KE. Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation. Trends Biochem Sci. 2018 Jan;43(1):61-74.
07. Lee JV, Berry CT, Kim K, Sen P, Kim T, Carrer A, Trefely S, Zhao S, Fernandez S, Barney LE, Schwartz AD, Peyton SR, Snyder NW, Berger SL, Freedman BD, Wellen KE. Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2+-NFAT signaling. Genes Dev. 2018 Apr 1;32(7-8):497-511.
08. Campbell SL and Wellen KE. Metabolic signaling to the nucleus in cancer. Mol Cell. 2018 Aug 2; 71(3):383-408.
09. Carrer A, Trefely S, Zhao S, Campbell S, Norgard RJ, Schultz KC, Sidoli S, Parris JLD, Affronti HC, Sivanand S, Egolf S, Sela Y, Trizzino M, Gardini A, Garcia BA, Snyder NW, Stanger BZ, Wellen KE. Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis. Cancer Discov. 2019 Mar;9(3):416-435.
10. Fernandez S, Viola JM, Torres A, Wallace M, Trefely S, Zhao S, Affronti HC, Gengatharan JM, Guertin DA, Snyder NW, Metallo CM, Wellen KE. Adipocyte ACLY facilitates dietary carbohydrate handling to maintain metabolic homeostasis in females. Cell Rep, 2019, May 28;27(9):2772-2784.
Lab Personnel
Aimee Farria - Postdoctoral Researcher
Joyce Liu, Graduate Student
Lyndsey Makinen - Program Coordinator lmakinen@upenn.edu
Mike Noji - Graduate Student
Laura Pinheiro - Graduate Student
Julianna Supplee - Graduate Student
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Read More about Eric S. Witze, Ph.D.Eric S. Witze, Ph.D.
Associate Professor
Eric S. Witze, Ph.D.
Associate Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 754 BRB II/III
Philadelphia PA, 19104-6160
T: 215-573-6301 F: 215-573-6725
Education
B.A. (Biology) University of California, Santa Barbara, 1994
Ph.D. (MCD Biology) University of California, Santa Barbara, 2003
Links
Current Research
The Witze Laboratory is interested in studying the mechanisms by which extracellular signaling controls polarized cell behavior and how alterations in these processes contribute to tumor initiation, metastasis, and drug sensitivity.
Witze Lab
My lab has focused on the regulation of cell signaling in cancer through protein palmitoylation in response to the non-canonical Wnt signaling pathway. The goal has been to develop a biochemically tractable system to begin to understand how non-canonical Wnt signaling regulates cell polarity Treatment of melanoma cells with purified Wnt5a induces a cell polarity phenotype involving the polarized localization of the cell adhesion molecule MCAM. We discovered that MCAM is palmitoylated and Wnt5a activation induces depalmitoylation. When the palmitoylated cysteine residue is mutated to glycine MCAM asymmetrically localizes independent of Wnt5a treatment. This demonstrated a novel pathway originating with Wnt5a binding and resulting in depalmitoylation of MCAM by the enzyme APT1. We have further shown that Wnt5a signaling induces phosphorylation of APT1 on specific serine residues and this modification increases APT1 activity and metastatic behavior of melanoma cells.
A second focus of the lab involves understanding how the palmitoyl-transferase DHHC20 palmitoylates the epidermal growth factor receptor (EGFR) on the C-terminal tail and suppresses EGFR activation. Inhibition of DHHC20 by shRNA decreases levels of EGFR palmitoylation and increases the amplitude of receptor signaling when stimulated with EGF. We mapped specific palmitoylation sites to cysteine residues in the C-terminal tail. The specific palmitoylation sites that were mapped by mass spectrometry reside in exons 26 and 27 that are sometimes deleted in lung cancer and glioblastoma. Deletion of the exons activate EGFR and can transform NIH3T3 cells. We similarly found that mutating the cysteine residues in exon 26 or 27 also activate EGFR and when expressed can transform cells. We hypothesize that loss of palmitoylation is the cause of receptor activation when exons 26 and 27 are deleted. Furthermore, when the palmitoylated cysteine residues are mutated the downstream MAPK/ERK pathway is activated and cells become dependent on EGFR signaling making cells sensitive to EGFR inhibitors. Unexpectedly, we also found that in lung cancer cells harboring mutations in EGFR that impart resistance to the EGFR inhibitor gefitinib when DHHC20 is inhibited these resistant cells become sensitive to gefitinib. We think this is an unprecedented approach to target cancer cell signaling.
The Witze lab is accepting applications for postdoctoral positions. Please email your CV to ewitze@upenn.edu.Selected Publications
01. Stypulkowski E, Asangani IA, and Witze ES: The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division. Science Signaling January 2018.
02. Sadeghi RS, Kulej K, Kathayat RS, Garcia BA, Dickinson BC, Brady DC, and Witze ES: Wnt5a Signaling Induced Phosphorylation Increases APT1 Activity and Promotes Melanoma Metastatic Behavior. eLife 7 April 2018.
03. Runkle KB, Kharbanda A, Stypulkowski E, Cao XJ, Wang W, Garcia BA, Witze ES: Inhibition of DHHC20-mediated EGFR palmitoylation creates a dependence on EGFR signaling. Molecular Cell 62(5): 385-96, May 2016.
04. Penzo-Méndez AI, Chen YJ, Li J, Witze ES, Stanger BZ: Spontaneous cell competition in immortalized mammalian cell lines. PLoS One 10(7): e0132437, July 2015.
05. Wang W, Snyder N, Worth AJ, Blair IA, Witze ES: Regulation of lipid synthesis by the RNA helicase Mov10 controls Wnt5a production. Oncogenesis 1(4): e154, June 2015 Notes: doi:10.1038/oncsis.2015.15.
06. Wang W, Runkle KB, Terkowski SM, Ekaireb RI, Witze ES: Protein depalmitoylation is induced by Wnt5a and promotes polarized cell behavior. The Journal of Biological Chemistry 290(25): 15707-16, June 2015.
07. Schwartz MP, Rogers RE, Singh SP, Lee JY, Loveland SG, Koepsel JT, Witze ES, Montanez-Sauri SI, Sung KE, Tokuda EY, Sharma Y, Everhart LM, Nguyen EH, Zaman MH, Beebe DJ, Ahn NG, Murphy WL, Anseth KS: A quantitative comparison of human HT-1080 fibrosarcoma cells and primary human dermal fibroblasts identifies a 3D migration mechanism with properties unique to the transformed phenotype. PLoS One 8(12): e81689, December 2013.
08. Londoño Gentile T, Lu C, Lodato PM, Tse S, Olejniczak SH, Witze ES, Thompson CB, Wellen KE: DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Molecular Cell Biology 33(19): 3864-78, October 2013.
09. Witze ES, Connacher MK, Houel S, Schwartz MP, Morphew MK, Reid L, Sacks DB, Anseth KS, Ahn NG: Wnt5a directs polarized calcium gradients by recruiting cortical endoplasmic reticulum to the cell trailing edge. Developmental Cell 26(6): 645-57, September 2013.
10. Witze ES, Field ED, Hunt DF, Rothman JH: C. elegans pur alpha, an activator of end-1, synergizes with the Wnt pathway to specify endoderm. Developmental Biology 327(1): 12-23, March 2009.
Lab Personnel
Yasmin Kadry - Postdoctoral Researcher
Lloyd Lee - Postdoctoral Researcher
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Read More about Xiaolu Yang, Ph.D.Xiaolu Yang, Ph.D.
Professor
Xiaolu Yang, Ph.D.
Professor
Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 654 BRB II/III
Philadelphia PA, 19104
T: 215-573-6739 F: (215) 573-6725
Education
B.Sc. (Physical Chemistry) Tsinghua University, 1985
Ph.D. (Genetics & Development) Columbia University, 1994
Links
Research Interests
The molecular and cellular mechanisms that protect against cancer and neurodegeneration. Key words: Cancer biology, p53, tumor suppression, metabolism, autophagy, stem cells, protein quality control, aging, neurodegenerative disease
Description of Research
Our lab studies cancer and neurodegenerative disease. Our current projects focus on two broad areas:
(1) The tumor suppressor p53, metabolism, and autophagy. We are interested in the regulation and functions of the preeminent tumor suppressor p53. Our results have revealed a role for p53 in modulating metabolic pathways that are critical for biosynthesis and redox balance. We are investigating the function of p53 as both a sentinel and a regulator for metabolic activities. We are also identifying and characterizing metabolic alterations that drive tumor initiation and progression. A recent extension of this research area is to define the role of metabolism and autophagy in stem cells, including embryonic stem cells and cancer stem cells.
(2) Protein quality control, aging, and neurodegeneration. Our lab recently identified two protein quality control (PQC) systems, which consist of tripartite motif (TRIM) proteins and poly-Asp/Glu (polyD/E) proteins, respectively. Unlike canonical PQC systems, these new systems are independent of ATP and are unique for animals (the TRIM system) or eukaryotes (the polyD/E system). Both systems are multifunctional and highly effective. We are investigating their mechanisms of action; their roles in aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis; and their utility in treating these diseases.
Selected Publications
Zhang Z.-Y., Harischandra D.S., Wang R., Ghaisas S., Zhao J.Y., McMonagle T.P., Zhu G., Lacuarta K.D., Song J., Trojanowski J.Q., Xu H., Lee V. M.-Y., Yang X.: TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease Science381: eadd6696, 2023 Notes: Comment in Science 381: 377-378, 2023.
Zhang Y., Xu Y., Lu W., Li J., Yu S., Brown E.J., Stanger B.Z., Rabinowitz J.D., Yang X.: G6PD-mediated increase in de novo NADP+ biosynthesis promotes antioxidant defense and tumor metastasis. Science Advances 8: eabo0404, 2022.
Zhu, G., Herlyn M., and Yang X.: TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. Nature Cell Biology 23: 978-991, 2021.
Zhang Y., Xu Y., Lu W., Ghergurovich J.M., Guo L., Blair I.A., Rabinowitz J.D., and Yang X.: Upregulation of antioxidant capacity and nucleotide precursor availability suffices for oncogenic transformation. Cell Metabolism 33: 94-109, 2021.
Huang L., Agrawal T., Zhu G., Yu S., Tao L., Lin J., Marmorstein R., Shorter J., Yang X.: DAXX represents a new type of protein-folding enabler. Nature 597: 132-137, 2021.
Zhu G., Harischandra D.S., Ghaisas S., Zhang P., Prall W., Huang L.,Maghames C., Guo L., Luna E., Mack K.L., Torrente M.P., Luk K.C., Shorter J., and Yang X.: TRIM11 Prevents and Reverses Protein Aggregation and Rescues a Mouse Model of Parkinson's Disease. Cell Reports 33: 108418, 2020.
Xu Y., Zhang Y., García-Cañaveras J.C., Guo L., Yu S., Blair I.A., Rabinowitz J.D., and Yang X.: Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells. Science 369: 397-403, 2020 Notes: Comment in Science 369: 373-374, 2020.
Chen L., Zhu G., Johns EM., Yang X.: TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14. Nature Communications 9: 1223, 2018.
Chen L., Brewer M., Guo L., Wang R., Jiang P., Yang X.: Enhanced Degradation of Misfolded Proteins Promotes Tumorigenesis. Cell Reports 18: 3143-3154, 2017.
Guo L., Giasson B.I., Glavis-Bloom A., Brewer M.D., Shorter J., Gitler A.D., and Yang X.: A cellular system that degrades misfolded proteins and protects against neurodegeneration. Molecular Cell 55: 15-30, 2014 Notes: Cover story and comment in Molecular Cell 55:1-3, 2014
Jiang P., Du W., Mancuso A., Wellen K. and Yang X.: Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493: 689-93, 2013.
Du W., Jiang P., Mancuso A., Stonestrom A., Brewer M.D., Minn A.J., Mak T.W., Wu M., and Yang X: TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nature Cell Biology 15: 991-1000, 2013 Notes: Cover story and comment in Nature Cell Biology 15:891-3, 2013.
Jiang P., Du W., Wang X., Mancuso A., Gao X., Wu M., and Yang X.: p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biology 13: 310-18, 2011 Notes: Cover story and comment in Nature Cell Biology 13:195-7, 2011.
Mei Y., Yong J., Liu H., Shi Y., Meinkoth J., Dreyfuss G., and Yang X.: tRNA binds to cytochrome c and inhibits caspase activation. Molecular Cell 37: 668-78, 2010 Notes: Cover story and comment in Molecular Cell 37: 591-2, 2010.
Kawadler H., Riley J.L., and Yang X.: The paracaspase MALT1 control caspase-8 activation during lymphocyte proliferation. Molecular Cell 31: 415-21, 2008.
Tang J., Qu L., Zhang J., Wang W., Michaelson J. S., Degenhardt Y., El-Deiry W.S., and Yang X.: Critical role for Daxx in regulating Mdm2. Nature Cell Biology 8: 855-62, 2006 Notes: Comment in Nature Cell Biology 8:790-1, 2006.
Hu S., Du M.-Q., Park S.-M., Alcivar A., Qu L., Gupta S., Tang J., Baens M., Ye H., Lee T., Marynen P., Riley J.L., and Yang X.: cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas. Journal of Clinical Investigation 116: 174-81, 2006 Notes: Comment in J Clin Invest. 116:22-6, 2006.
Lab Personnel
Lyndsey Makinen - Program Coordinator lmakinen@upenn.edu
Kenzo Lacuarta - Research Specialist / Lab Manager
Jiale Wu, Ph.D. - Postdoctoral Researcher
Zi-Yang Zhang - Ph.D. - Postdoctoral Researcher
Yujin Xiang - Ph.D. - Postdoctoral Researcher
Jiajia Wang - Ph.D. - Postdoctoral Researcher
Ruifang Wang - Ph.D. - Postdoctoral Researcher
Sixiang Yu - Ph.D. - Postdoctoral Researcher
Kai Huang - Ph.D. - Postdoctoral Researcher
Rachel Ou – Undergraduate Student Researcher
Steven Su – Undergraduate Student Researcher
Megan Zhang – Undergraduate Student Researcher
Hong Yu Liu – Undergraduate Student Researcher
Affiliated Faculty
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Read More about James Alwine, Ph.D., FAAM, FAAASJames Alwine, Ph.D., FAAM, FAAAS
Emeritus Professor
James Alwine, Ph.D., FAAM, FAAAS
Emeritus Professor
Contact Info
Education
B.S. (Chemistry) Elizabethtown College, 1969
Ph.D. (Biological Chemistry) The Milton S. Hershey Medical Center of the Pennsylvania State University, 1974
Links
Career
Dr. Alwine’s 37 year career at Penn has covered many aspects of molecular virology including the effects of viruses on cellular transcription, mRNA processing, stress responses, metabolism and the relationship of these effects to the genesis or propagation of cancer. He has made numerous significant contributions for which he was elected Fellow of the American Academy of Microbiology, and Fellow of the American Association for the Advancement of Science. His recent research interests have been in the area of defining the microbiome of the tumor microenvironment, data that may provide diagnostic and prognostic biomarkers.
Dr. Alwine became Emeritus in 2016 and no longer runs a research laboratory. However, he remains active as a department member and mentor/advisor to anyone who asks.Selected Publications
1. Banerjee S, Tian T, Wei Z, Peck KN, Shih N, Chalian AA, O'Malley Jr BW, Weinstein GS, Feldman MD, Alwine JC, Robertson ES. Microbial Signatures Associated with Oropharyngeal and Oral Squamous Cell Carcinomas. Scientific Reports. 2017 (in press)
2. Banerjee S, Tian T, Wei Z, Shih N, Feldman MD, Coukos G, Alwine JC, Robertson ES. The ovarian cancer oncobiome. Oncotarget. 2017 Mar 30. doi: 10.18632/oncotarget.16717.
3. Vysochan A, Sengupta A, Weljie AM, Alwine JC, Yu Y. ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1528-E1535. doi: 10.1073/pnas.1614268114.
4. Banerjee S, Peck KN, Feldman MD, Schuster MG, Alwine JC, Robertson ES. Identification of fungal pathogens in a patient with acute myelogenic leukemia using a pathogen detection array technology. Cancer Biol Ther. 2016 Apr 2;17(4):339-45. doi: 10.1080/15384047.2015.1121349.
5. Banerjee S, Wei Z, Tan F, Peck KN, Shih N, Feldman M, Rebbeck TR, Alwine JC, Robertson ES. Distinct microbiological signatures associated with triple negative breast cancer. Sci Rep. 2015 Oct 15;5:15162. doi: 10.1038/srep15162.
6. Baldwin DA, Feldman M, Alwine JC, Robertson ES. Metagenomic assay for identification of microbial pathogens in tumor tissues. MBio. 2014 Sep 16;5(5):e01714-14. doi: 10.1128/mBio.01714-14.
7. Yu Y, Maguire TG, Alwine JC. ChREBP, a glucose-responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus-infected cells. Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1951-6. doi: 10.1073/pnas.1310779111.
8. Shenk T, Alwine JC. Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways. Annu Rev Virol. 2014 Nov;1(1):355-74. doi: 10.1146/annurev-virology-031413-085425.
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Read More about Noam Auslander, Ph.D.Noam Auslander, Ph.D.
Assistant Professor
Noam Auslander, Ph.D.
Assistant Professor
Molecular & Cellular Oncogenesis Program, Ellen and Ronald Caplan Cancer Center
Contact Information
3601 Spruce St 218-G
Philadelphia, PA 19104
T: 215-495-6937
Education
BSc (Computer Science and Biology) Tel Aviv University, Tel Aviv, Israel, 2014
PhD (Computer Science) University of Maryland, College Park, MD, 2018
Links
Current Research
Our lab develops computational methods to better understand how cancer develops through genetic changes and pathogenic infections. We develop integrative deep learning sequence analysis frameworks to identify new microbial sequences in cancer. We apply these methods to study microbial genes and proteins that correlate with tumor progression and with clinical outcomes.
Our lab also develops interpretable machine learning frameworks to identify treatment response biomarkers and understand the mechanisms underlying response or resistance. As a computational (dry) lab, we benefit from multiple ongoing collaborative studies, aiming to investigate microbial and genomic biomarkers of cancer treatment response and metastases.Selected Publications
01. Andrew Patterson, Noam Auslander. Mutated Processes Predict Immune Checkpoint Inhibitor Therapy Benefit in Metastatic Melanoma. In press, Nature Communications
02. Gauri Mirji, Alison Worth, Sajad Ahmad Bhat, Mohamed El Sayed, Sarah Kim Reiser, Toshitha Kannan, Aaron R Goldman, Hsin-Yao Tang, Mohammad Damra, Qin Liu, Noam Auslander, Chi V Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Z Stanger, Rahul S Shinde. A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer. In press, Science Immunology.
03. Ayal B. Gussow, Eugene V. Koonin, Noam Auslander. Identification of combinations of somatic mutations that predict cancer survival and immunotherapy benefit. NAR Cancer, May 2021.
04. Noam Auslander, Ayal B Gussow, Eugene V Koonin. Incorporating Machine Learning into Established Bioinformatics Frameworks. International Journal of Molecular Sciences, March 2021.
05. Noam Auslander, Ayal B Gussow, Sean Benler, Yuri I Wolf, Eugene V Koonin. Seeker: Alignment-free identification of bacteriophage genomes by deep learning. Nucleic Acid Research, October 2020
06. Ayal B. Gussow, Noam Auslander, Guilhem Faure, Yuri I. Wolf, Feng Zhang, Eugene V. Koonin. Genomic determinants of pathogenicity in SARS-CoV-2 and other human coronaviruses. Proceedings of the National Academy of Sciences, June 2020
07.Noam Auslander, Yuri I Wolf, Eugene V Koonin. Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability. Nature Communications, March 2020.
08. Noam Auslander, Yuri I Wolf, Eugene V Koonin. In silico learning of tumor evolution through mutational time series. Proceedings of the National Academy of Sciences, April 2019.
09. Noam Auslander, Gao Zhang, Joo Sang Lee, Dennie T. Frederick, Benchun Miao, Tabea Moll, Tian Tian, Zhi Wei, Ryan J. Sullivan, Sanna Madan, Genevieve Boland, Keith Flaherty, Meenhard Herlyn, Eytan Ruppin. Robust prediction of therapeutic response to immune checkpoint blockade therapy in metastatic melanoma. Nature Medicine, August 2018.
10. Noam Auslander, Chelsea E. Cunningham, Behzad M. Toosi, Emily McEwen, Keren Yizhak Frederick S. Vizeacoumar, Sreejit Parameswaran, Nir Gonen, Andrew Freywald, Franco J. Vizeacoumar, Eytan Ruppin. An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer. Molecular Systems Biology, December 2017
Lab Personnel
Abdurrahman Elbasir - Postdoctoral Researcher
Andrew Patterson - PhD Student
Konstantinos Tsingas - MSc Student
Daniel Schaffer - Undergraduate Student
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Read More about George Burslem, Ph.D.George Burslem, Ph.D.
Assistant Professor
George Burslem, Ph.D.
Assistant Professor
Department of Biochemistry and Biophysics
Cancer Biology
Member, Epigenetics Institute
Contact Info
1013 Stellar Chance Laboratories
422 Curie Boulevard
Philadelphia PA, 19104-6056
George.Burslem@pennmedicine.upenn.edu
Education
MSci (Chemistry) University of Bristol, UK, 2011
Ph.D. (Chemical Biology) University Leeds, UK, 2015
Links
Current Research
Our current research is focussed on the development of novel chemical approaches to modulate lysine post-translational modifications. This includes both synthetic and protein engineering approaches to understand lysine modifications as well as chemical biology approaches to modulate them as a potential therapeutic approach.
Burslem Lab
Post-translational modifications (PTMs) are key modulators of protein function and are crucial for the successful function of a cell. They can act as methods for signal transduction, alter the localization of a protein or signal that a protein is no longer required, as well as many other functions. The most widely studied PTM is phosphorylation of serine, threonine and tyrosine residues but reversible covalent modifications of lysine residues can have equally important functions. For example, acetylation of lysine residues is the second most observed PTM, after phosphorylation.
The Burslem lab is interested in developing chemical tools to understand and modulate lysine post-translational modifications, specifically acetylation and ubiquitination. The laboratory is particularly interested in novel pharmacological approaches to modulate post-translational modifications which regulate gene expression and protein stability with a focus on understanding and treating haematological malignancies. We employ a multidisciplinary approach including synthetic chemistry, biochemistry, biophysics and cell biology to probe biological systems in cancer biology.
Selected Publications
01. Burslem, G.M., Schultz, A.R., Bondeson, D.P., Eide, C.A., Savage Stevens, S.L., Druker, B.J., and Crews, C.M. (2019). Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation. Cancer Res 79, 4744-4753.
02. Burslem, G.M., Song, J., Chen, X., Hines, J., and Crews, C.M. (2018c). Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion. Journal of the American Chemical Society 140, 16428-16432.
03. Burslem, G.M., Smith, B.E., Lai, A.C., Jaime-Figueroa, S., McQuaid, D.C., Bondeson, D.P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018b). The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chemical Biology 25, 67-77.e63.
04. Bondeson, D.P., Smith, B.E., Burslem, G.M., Buhimschi, A.D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B.D., Ishchenko, A., and Crews, C.M. (2018). Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chemical Biology 25, 78-87.
05. Burslem, G.M., Ottis, P., Jaime-Figueroa, S., Morgan, A., Cromm, P.M., Toure, M., and Crews, C.M. (2018a). Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships. ChemMedChem 13, 1508-1512.
06. Burslem, G.M., Kyle, H.F., Nelson, A., Edwards, T.A., and Wilson, A.J. (2017). Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions. Chemical Science 8, 4188-4202.
07. Grison, C.M., Burslem, G.M., Miles, J.A., Pilsl, L.K.A., Yeo, D.J., Imani, Z., Warriner, S.L., Webb, M.E., and Wilson, A.J. (2017). Double quick, double click reversible peptide “stapling”. Chemical Science 8, 5166-5171.
08. Burslem, G.M., Kyle, H.F., Breeze, A.L., Edwards, T.A., Nelson, A., Warriner, S.L., and Wilson, A.J. (2016). Towards “bionic” proteins: replacement of continuous sequences from HIF-1α with proteomimetics to create functional p300 binding HIF-1α mimics. Chemical Communications 52, 5421-5424.
09. Kyle, H.F., Wickson, K.F., Stott, J., Burslem, G., Breeze, A.L., Tiede, C., Tomlinson, D.C., Warriner, S., Nelson, A., Wilson, A., et al. (2015). Exploration of the HIF-1[small alpha]/p300 interface using peptide and Adhiron phage display technologies. Molecular BioSystems.
10. Burslem, G.M., Kyle, H.F., Breeze, A.L., Edwards, T.A., Nelson, A., Warriner, S.L., and Wilson, A.J. (2014). Small-Molecule Proteomimetic Inhibitors of the HIF-1α–p300 Protein–Protein Interaction. ChemBioChem 15, 1083-1087.
Lab Personnel
Jenna Beyer - Graduate Student
Adam Green - Postdoctoral Researcher
Karine Kasti - Research Specialist
Nicole Raniszewski - Graduate Student
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Read More about Robert Babak Faryabi, Ph.D.Robert Babak Faryabi, Ph.D.
Associate Professor
Robert Babak Faryabi, Ph.D.
Associate Professor
Department of Pathology and Laboratory Medicine
Associate Investigator, Abramson Family Cancer Research Institute
Contact Information
421 Curie Boulevard, 553 BRB II/III
Philadelphia PA, 19104-6160
T: 215-573-8220
faryabi@pennmedicine.upenn.edu
Education
BSc (Electrical Engineering) Sharif University Of Technology, Tehran, Iran, 1995.
MSc (Electrical Engineering) Sharif University Of Technology, Tehran, Iran, 1997
PhD (Computational Biology) Texas A&M University, College Station, TX, 2009
Links
Research Interest
Our lab focuses on understanding the mechanism of epigenetic dysregulation in cancer. We are particularly interested in elucidating how oncogenic signals contribute to tumor pathogenicity through epigenetic misregulation, and to leverage this mechanistic understanding for improved treatments.
The lab mainly studies cancers with frequent mutations in Notch receptor families. We use combination of wet and dry techniques to understand how oncogenic Notch drives regulatory program in these tumors. Our lab benefits from various established data-rich assays and combine them with novel technologies such as chromatin conformation and single cell genomics to elucidate the mechanisms of epigenetic dysregulation in Notch-driven tumors at both population and single cell levels.
As a member of Center for Personalized Diagnostics, we are also developing computational oncology frameworks to enrich clinical significance of diagnostic tumor genomics. Our goal is to advance the paradigm of personalized medicine by leveraging big data analytics to drive correlation between the tumor genomes and clinical covariates.
To learn more about our research interests and specifics of our projects check our lab's website
Selected Publications01. Petrovic J* Zhou Y*, Fasolino M, Goldman N, Schwartz GW, Mumbach MR, Nguyen SC, Rome KS, Sela Y, Zapataro Z, Blacklow SC, Kruhlak MJ, Shi J, Aster JC, Joyce EF, Little SC, Vahedi G, Pear WS, Faryabi RB.: Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques. Molecular Cell. 73(6):1174-1190.e12. doi: 10.1016/j.molcel.2019.01.006, Mar 2019.
02. Schwartz GW, Manning BS, Zhou Y, Velu PD, Bigdeli A, Astles R, Lehman AW, Morrissette JJ, Perl AE, Li M, Carroll M, Faryabi RB. : Classes of ITD predict outcomes in AML patients treated with FLT3 inhibitors. Clinical Cancer Research Jan 2019 Notes: 15;25(2):573-583. doi: 10.1158/1078-0432.CCR-18-0655.
03. Schwartz G, Petrovic J, Zhou Y, Faryabi RB: Differential Integration of Transcriptome and Proteome Identifies Pan-cancer Prognostic Biomarkers. Frontiers in Genetics 9:205, June 2018 Notes: doi: 10.3389/fgene.2018.00205.
04. Ryan RJH*, Petrovic J*, Rausch DM, Zhou Y, Lareau C, Kluk MJ, Christie AL, Lee W, Guo B, Donohue LKH, Gillespie S, Nardi V, Hochberg EP, Blacklow SC, Weinstock DM, Faryabi RB, Bernstein BE+, Aster JC+, Pear WS+: A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Reports 21(3): 784-797, October 2017 Notes: doi: 10.1016/j.celrep.2017.09.066.
05. Rolland DC, Basrur V, Jeon Y-K, McNeil-Schwalm C, Fermin D, Conlon K, Zhou Y, Ng SY, Tsou C-C, Brown NA, Thomas DG, Bailey NG, Omenn GS, Nesvizhskii AI, Root DE, Weinstock DM, Faryabi RB, Lim MS, Elenitoba-Johnson KSJ: Functional Proteogenomics Reveals Biomarkers and Therapeutic Targets in Lymphomas. Proceedings of the National Academy of Sciences 11(24): 6581-6586, May 2017.
06. Barlow JH*, Faryabi RB*, Callen E, Wong N, Malhowski A, Chen H-T, Gutierrez-Cruz G, Sun H-W, McKinnon P, Wright G, Casellas R, Robbiani DF, Staudt L, Fernandez-Capetillo O, Nussenzweig A : Identification of Early Replicating Fragile Sites that Contribute to Genome Instability. Cell 152(3): 620-32, January 2013 Notes: *co-first author.
07. Santos MA, Faryabi RB, Ergen AV, Day AM, Malhowski A, Canela A, Onozawa M, Lee J-E, Callen E, Gutierrez-Martinez P, Chen H-T, Wong N, Finkel N, Deshpande A, Sharrow S, Rossi DJ, Ito K, Ge K, Aplan PD, Armstrong SA, Nussenzweig A: DNA-damage-induced Differentiation of Leukaemic Cells as an Anti-cancer Barrier. Nature 514(7520): 107-11, October 2014.
08. Callen E, Faryabi RB, Luckey M, Hao B, Daniel JA, Yang W, Sun H-W, Dressler G, Peng W, Chi H, Ge K, Krangel MS, Park J-H, Nussenzweig A: The DNA Damage- and Transcription-associated Protein Paxip1 Controls Thymocyte Development and Emigration. Immunity 37(6): 971-85, December 2012.
09. Faryabi RB, Vahedi G, Datta A, Chamberland J-F, Dougherty ER: Recent Advances in the Control of Markovian Gene Regulatory Networks. Current Genomics 10(7): 540-547, November 2009.Lab Personnel
Ashkan Bigledi - Gradute Student
Jelena Petrovic - Graudate Student
Gregory Schwartz - Postdoctoral Researcher
Yeqiao Zhou - Graduate Student
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Read More about Terence Gade, M.D., Ph.D.Terence Gade, M.D., Ph.D.
Associate Professor
Terence Gade, M.D., Ph.D.
Associate Professor
Department of Radiology
Associate Investigator, Abramson Family Cancer Research Institute
Contact Information
421 Curie Boulevard, 652 BRB II/III
Philadelphia, PA 19104
T: 215-573-9756 F: 215-573-6725 Lab: 215-573-9755
Education
B.A. (Bachelor of Arts with High Honors and Distinction) University of Michigan, Ann Arbor, MI, 1998
Ph.D. (Doctorate of Philosophy in Biophysics) Weill Graduate School of Medical Sciences of Cornell University, New York, NY, 2006
M.D. (Doctor of Medicine) Weill Medical College of Cornell University, New York, NY, 2008
Post-Graduate Training
3M Summer Research Fellow, University of Michigan, Department of Chemistry, Ann Arbor, MI, 1996-1996Intern-General Surgery, Lankenau Hospital, Wynnewood, PA, 2008-2009
Resident in Diagnostic Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 2009-2014
Post-Doctoral Fellow, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA, 2011-2013
Research Chief Resident, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 2012-2014
Fellow in Interventional Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 2014-2015
Certifications
Diplomate, American Board of Radiology, 2014Links
Research Interests
The research interests of our laboratory lie at the intersection of image-guided interventions, cancer and vascular biology, and molecular and advanced 3D imaging.
Cancer Biology
Interventional oncology represents the fourth arm of cancer therapy offering locoregional treatment approaches for a variety of malignancies. These approaches apply minimally invasive procedures to target cancer using percutaneous or endovascular techniques. In using imaging to directly modulate the tissue environment of the targeted cancer, these techniques provide a unique lens through which to study the tumor microenvironment. The tumor microenvironment comprises complex interactions between cancer cells and the stroma including immune cells, fibroblasts, the extracellular matrix as well as vascular networks. Our interests focus broadly on the study of the tumor microenvironment and how alterations in the tumor microenvironment affect subpopulations of cancer cells as well as how they influence the interactions of stromal cells with the tumor. Given that these are in vivo phenomena, the development of novel in vivo molecular imaging strategies is implicit in order to characterize these interactions. These studies will lead to new therapeutic targets and imaging strategies that can be applied for new and improved interventions. Current projects in the lab emphasize this goal in the context of a variety of disciplines including molecular biology, metabolism, immunology, bioengineering and imaging physics.
Selected Publications
01. Hunt S, Gade TP, Soulen MC, Pickup S, Sehgal C.: Antivascular ultrasound therapy: MR validation and activation of immune response in murine melanoma. Journal of Ultrasound in Medicine. 34(2): 275-87, February 2015.
02. C. N. Weber S. Hunt B. H. Ge T. P. Gade G. Nadolski: Translational rat model of arteriovenous fistula for the study of the pathophysiology and molecular imaging of dialysis access stenosis and development of endovascular therapies. Society for Interventional Radiology 2015 Notes: Poster Presentation.
03. T. P. Gade E. Tucker S. Hunt M. Nakazawa B. Krock W. Wong G. Nadolski T. Clark E. Furth M. Schnall M. C. Soulen C. Simon: Targeting the Metabolic Stress Response in Hepatocellular Carcinoma to Potentiate TACE-Induced Ischemia. Society for Interventional Radiology 2015 Notes: Poster Presentation.
04. M. Hsu C. N. Weber M. Mohammed T. P. Gade S. Hunt G. Nadolski T. Clark: Thermal changes during rheolytic mechanical thrombectomy. Journal of Vascular and Interventional Radiology 27(6), June 2016.
05. Mehrdad Pourfathi Terence Gade Stephen Hunt Stephen Pickup Anthony Mancuso Mitchell Schnall Anthony Mancuso Michael Soulen Stephen Kadlecek Neil Harrison Gregory Nadolski Rahim Rizi Mitchell Schnall Michael Soulen Celeste Simon: Quantification of TAE-induced Alterations in Tumor Metabolism using Hyperpolarized. International Society for Magnetic Resonance in Medicine 2015 Notes: Poster Presentation.
06. G. Nadolski M. Mohammed E. Mills-Robertson T. P. Gade M. C. Soulen S. Hunt: Effect of Neoadjuvant Locoregional Therapy on Outcomes of Orthotopic Liver Transplant for Hepatocellular Carcinoma. Society for Interventional Radiology 2015 Notes: Poster Presentation.
07. T. P. Gade A. Mancuso M. Pourfathi S. Kadlecek S. Pickup N. Harrison S. Hunt G. Nadolski R. Rizi M. Schnall M. C. Soulen C. Simon: Real-Time Metabolic Imaging of TAE-Induced Alterations in Tumor Metabolism Using Dynamic Nuclear Polarization Carbon-13 Magnetic Resonance Spectroscopy In Vivo. Society for Interventional Radiology 2015 Notes: Poster Presentation.
08. C. T. Duncan T. P. Gade S. Hunt R. Shlansky-Goldberg G. Nadolski: Outcomes of Percutaneous Cholecystostomy in the Presence of Ascites. Journal of Vascular and Interventional Radiology 27(4): 562-566, April 2016.
09. Ge, Benjamin Weber, Charles Nadolski, Gregory Gade,Terence P. Hunt, Stephen Soulen, Michael C. Itkin, Maxim: Size and Shape Adjustable Coaxial Electrochemical Ablation – In Vitro and Ex Vivo Evaluation of a Novel Experimental Technique. Society for Interventional Radiology 2015 Notes: Poster Presentation.
10. Li B, Qiu B, Lee, DSM, Walton ZE, Ochocki JD, Mathew LK, Mancuso AM, Gade TP, Nissim I, Keith B, Simon MC.: Fructose-1,6 bisphosphatase 1 is a Metabolic Tumor Suppressor in Renal Carcinoma. Nature 513(7517): 251-5, September 2014.Lab Personnel
Dan Ackerman - Staff Scientist
Omar Johnson - Research Specialist
Wuyan (Jaycee) Li - Research Specialist
Lyndsey Makinen - Program Coordinator lmakinen@upenn.edu
Gabrielle Pilla - Graduate Student
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Read More about Alexander C Huang, M.D.Alexander C Huang, M.D.
Assistant Professor
Alexander C Huang, M.D.
Assistant Professor
Department of Medicine
Contact Information
421 Curie Blvd, 714 BRB II/III
Philadelphia, PA 19104
alexander.huang@pennmedicine.upenn.eduEducation
B.S. (Science, Biomedical Engineering ) Johns Hopkins University , 2005
M.D. Mount Sinai School of Medicine , 2010Selected Publications
Ou L, Liu S, Wang H, Guo Y, Guan L, Shen L, Luo R, Elder DE, Huang AC, Karakousis G, Muira J, Mitchell T, Schuchter L, Amaravadi R, Flowers A, Mou H, Yi F, Guo W, Ko J, Chen Q, Tian B, Herlyn M, Xu X: Patient-derived melanoma organoid models facilitate the assessment of immunotherapies. EBio Medicine 92: 104614, June 2023.
Wang G, Lyudovyk O, Kim JY, Lin YH, Elhanati Y, Mathew D, Wherry EJ, Herati RS, Greenplate AR, Greenbaum B, Vardhana SA, Huang AC.: High-throughput interrogation of immune responses using the Human Immune Profiling Pipeline. STAR Protocol 4: 102289, May 2023.
Shah PD, Huang AC, Xu X, Orlowski R, Amaravadi RK, Schuchter LM, Zhang P, Tchou J, Matlawski T, Cervini A, Shea J, Gilmore J, Lledo L, Dengel K, Marshall A, Wherry EJ, Linette GP, Brennan A, Gonzalez V, Kulikovaskaya I, Lacey SF, Plesa G, June CH, Vonderheide RH, Mitchell TC.: Phase 1 trial of autologous RNA-electroporated cMET-directed CAR T cells administered intravenously in patients with melanoma and breast carcinoma. Cancer Res Commun 3: 821-829, May 2023.
Cosgriff CV, Miano TA, Mathew D, Huang AC, Giannini HM, Kuri-Cervantes L, Pampena MB, Ittner CAG, Weisman AR, Agyekum RS, Dunn TG, Oniyide O, Turner AP, D'Andrea K, Adamski S, Greenplate AR, Anderson BJ, Harhay MO, Jones TK, Reilly JP, Mangalmurti NS, Shashaty MGS, Betts MR, Wherry EJ, Meyer NJ: Validating a Proteomic Signature of Severe COVID-19. Crit Care Explor 4: 30800, December 2022.
Giles JR, Ngiow SF, Manne S, Baxter AE, Khan O, Wang P, Staupe R, Abdel-Hakeem MS, Huang H, Mathew D, Painter MM, Wu JE, Huang YJ, Goel RR, Yan PK, Karakousis GC, Xu X, Mitchell TC, Huang AC, Wherry EJ.: Shared and distinct biological circuits in effector, memory and exhausted CD8(+) T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat Immunol Oct 2022.
Herati RS, Knorr DA, Vella LA, Silva LV, Chilukuri L, Apostolidis SA, Huang AC, Muselman A, Manne S, Kuthuru O, Staupe RP, Adamski SA, Kannan S, Kurupati RK, Ertl HCJ, Wong JL, Bournazos S, McGettigan S, Schuchter LM, Kotecha RR, Funt SA, Voss MH, Motzer RJ, Lee CH, Bajorin DF, Mitchell TC, Ravetch JV, Wherry EJ.: PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine. Nat Immunol August 2022.
Lyudovyk O, Kim JY, Qualls D, Hwee MA, Lin YH, Boutemine SR, Elhanati Y, Solovyov A, Douglas M, Chen E, Babady NE, Ramanathan L, Vedantam P, Bandlamudi C, Gouma S, Wong P, Hensley SE, Greenbaum B, Huang AC, Vardhana SA.: Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses. Cancer Cell 40: 738-753, Jul 2022.
Huang AC, Zappasodi R.: A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat Immunol May 2022.
Apostolidis SA, Sarkar A, Giannini HM, Goel RR, Mathew D, Suzuki A, Baxter AE, Greenplate AR, Alanio C, Abdel-Hakeem M, Oldridge DA, Giles JR, Wu JE, Chen Z, Huang YJ, Belman J, Pattekar A, Manne S, Kuthuru O, Dougherty J, Weiderhold B, Weisman AR, Ittner CAG, Gouma S, Dunbar D, Frank I, Huang AC, Vella LA; UPenn COVID Processing Unit, Reilly JP, Hensley SE, Rauova L, Zhao L, Meyer NJ, Poncz M, Abrams CS, Wherry EJ.: Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19. Front Immunol 13: 834988, Mar 2022.
Mehnert JM, Mitchell TC, Huang AC, Aleman TS, Kim BJ, Schuchter LM, Linette GP, Karakousis GC, Mitnick S, Giles L, Carberry M, Frey N, Kossenkov A, Groisberg R, Hernandez-Aya LF, Ansstas G, Silk AW, Chandra S, Sosman JA, Gimotty PA, Mick R, Amaravadi RK.: BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma. Clin Cancer Res 28: 1098-1106, Mar 2022. -
Read More about Brian D. Keith, Ph.D.Brian D. Keith, Ph.D.
Adjunct Professor
Brian D. Keith, Ph.D.
Adjunct Professor
Associate Investigator, Abramson Family Cancer Research Institute
Contact Info
421 Curie Boulevard, 453 BRB II/III
Philadelphia PA, 19140
T: (215) 746-5533 F: (215) 746-5511
Education
Sc.B. (Biology) Brown University, 1980
Ph.D. (plant Molecular Biology) The Rockefeller University, 1987
Links
Biomedical Postdoctoral Programs
Current Research
Dr. Keith collaborates with Dr. M. Celeste Simon to study how cells respond to oxygen deprivation (hypoxia), which occurs naturally as tissue (or tumor) growth outstrips its blood supply. We generate mouse models in which genes encoding critical components of the hypoxic response pathway are mutated. These novel genetic tools offer unique insights into the mechanisms by which hypoxia regulates cancer cell function, and tumor growth. In addition to research, Dr. Keith coordinates the educational activities of AFCRI faculty at the medical, graduate, and undergraduate level. Most recently, Dr. Keith has developed an undergraduate course on the biological origins of cancer (Cancer Cell Biology - Biol407), which is offered annually through the Department of Biology.
Keith Lab
Dr. Keith received his Ph.D. from The Rockefeller University. He completed postdoctoral training with Dr. Gerald R. Fink at the Whitehead Institute for Biomedical Research, after which he became an Assistant Professor in the Departments of Molecular Genetics and Cell Biology, and Medicine at the University of Chicago. Dr. Keith joined the AFCRI in 1999 as Director of Education and is currently an Associate Investigator, and Adjunct Professor in the Department of Cancer Biology.
Selected Publications
01. Skuli N, Majmundar A, Mesquita R, Quinn Z, Runge A, Liu L, Gruber M, Kim M, Liang J, Schenkel S, Yodh A, Keith B, and Simon MC Endothelial hypoxia inducible factor-2a (HIF-2a) regulates murine pathological angiogenesis and revascularizaiton. J. Clin. Invest. 122: 1427-43. 2012.
02. Keith B, Johnson RS, and Simon MC HIF1a and HIF2a: sibling rivalry in hypoxic tumor growth and progression. Nat. Rev. Cancer, 12: 9-22. 2012.
03. Mazumdar J, Hickey MM, Pant DK, Durham A, Sweet-Cordero A, Vachani A, Jacks T, Chodosh LA, Kissil JK, Simon MC, and Keith B. HIF-2a deletion promotes Kras-driven lung tumor development. Proceedings of the National Academy of Sciences USA, 107: 14182-14187. 2010.
04. Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, and Simon MC. Hypoxia factor 2-alpha regulates macrophage function in mouse models of acute and tumor inflammation. Journal of Clinical Investigation 120: 2699-2714. 2010.
05. Bertout, J., Mamundar, A.J., Gordan, J.D., Lam, J.C., Ditsworth, D., Keith, B., Brown, E.J., Nathanson, K.L., and Simon, M.C. HIF2a inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proceedings of the National Academy of Sciences USA, 106: 14391-14396. 2009.
06. Skuli N, Liu L, Wang T, Patel S, Runge A, Iruela-Arispe L, Simon MC, Keith B. Endothelial deletion of Hypoxia Inducible Factor-2alpha (HIF-2a) alters vascular function and tumor angiogenesis. Blood, 114: 469-477. 2009.
07. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulanot S, Peyssonnaux C. HIF-2alpha but not HIF-1alpha is a key regulator of iron absorption. J. Clin. Invest. 119: 1159-1166. 2009.
08. Gordan JD, Lal P, Letrero R, Parekh KN, Oquendo CE, Dondeti V, Greenberg RA, Flaherty KT, Rathmell, WK, Keith B, Simon MC, Nathanson KL. HIF-a effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14: 435-446. 2008.
09. Simon MC & Keith B. The role of oxygen availability in embryonic development and stem cell function. Nature Reviews: Molecular Cell Biology 9: 285-296. 2008.
10. Keith B and Simon MC. Hypoxia Inducible Factors, stem cells, and cancer. Cell 129: 465-472. 2007.
