Junwei Shi, Ph.D.
Philadelphia, PA 19104-6160
Sun Yat-sen University (China), 2008.
Ph.D. (Molecular and Cellular Biology)
Stony Brook University, SUNY, 2016.
Description of Research ExpertiseCurrent Research
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and causes up to 800,000 deaths annually worldwide. My lab focuses on understanding molecular pathways that support HCC growth. A major clinical challenge for HCC is that most patients are diagnosed at advanced stages, and no curative treatments are currently available. The multikinase inhibitor Sorafenib is the only approved therapy for late stage HCC, which confers only an approximately 3-month median survival benefit.
Current areas of interest within the lab include: (1) Defining the functional importance of epigenetic regulators in HCC, (2) Dissecting the signal transduction pathways that are required for HCC maintenance, and (3) Developing new functional genomic tools.
While whole exome sequencing of HCC cancer genome revealed many oncogene mutations, none of these genetic alterations lead to directly actionable therapeutic opportunities. A challenge in the HCC research community is to reveal non-oncogene dependencies that could be exploited with targeted therapeutics. A major objective of the lab is to annotate and dissect these non-oncogene vulnerabilities in HCC. To approach this, we will use our recently developed domain-focused CRISPR genetic knockout screening technology. This method directs the CRISPR-mediated mutagenesis to gene sequences encoding critical protein domains, which generates larger fraction of functional null alleles thus increases the severity in a phenotypic genetic screening. 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 with functional genomics screening, biochemical, and pre-clinical mouse models of HCC approaches, we will investigate the aberrant transcription signaling networks of HCC and explore them as potential therapeutic opportunities in HCC. 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 HCC that are therapeutically tractable.
Krista Budinich, Research Specialist
Zhendong Cao, Graduate Researcher
Emily Duffner, Research Specialist
Rodrigo Gier, Research Specialist
Brandon Hayes, Graduate Student
Henry Sanchez, Graduate Student
Sydney Shaffer, Postdoctoral Researcher
Deb Sneddon, Administrative Coordinator
Nancy Yang, Undergraduate Researcher
Selected PublicationsEhrenhöfer-Wölfer K, Puchner T, Schwarz C, Rippka J, Blaha-Ostermann S, Strobl U, Hörmann A, Bader G, Kornigg S, Zahn S, Sommergruber W, Schweifer N, Zichner T, Schlattl A, Neumüller RA, Shi J, Vakoc CR, Kögl M, Petronczki M, Kraut N, Pearson MA, Wöhrle S: SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines. Scientific Reports 9(1): 11661, Aug 2019.
Bell CC, Fennell KA, Chan YC, Rambow F, Yeung MM, Vassiliadis D, Lara L, Yeh P, Martelotto LG, Rogiers A, Kremer BE, Barbash O, Mohammad HP, Johanson TM, Burr ML, Dhar A, Karpinich N, Tian L, Tyler DS, MacPherson L, Shi J, Pinnawala N, Yew Fong C, Papenfuss AT, Grimmond SM, Dawson SJ, Allan RS, Kruger RG, Vakoc CR, Goode DL, Naik SH, Gilan O, Lam EYN, Marine JC, Prinjha RK, Dawson MA: Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nature communications 10(1): 272, June 2019.
Xianjiang Lan, Eugene Khandros, Peng Huang, Scott A. Peslak,1 Saurabh K. Bhardwaj, Jeremy D. Grevet, Osheiza Abdulmalik, Hongxin Wang, Cheryl A. Keller, Belinda Giardine, Josue Baeza, Emily R. Duffner, Osama El Demerdash, Xiaoli S. Wu, Christopher R. Vakoc, Benjamin A. Garcia, Ross C. Hardison, Junwei Shi, and Gerd A. Blobel: The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells. Blood Advances 3(10): 1586-1597, May 2019.
Jelena Petrovic, Yeqiao Zhou, Maria Fasolino, Naomi Goldman, Gregory W. Schwartz, Maxwell R. Mumbach, Son C. Nguyen, Kelly S. Rome, Yogev Sela, Zachary Zapataro, Stephen C. Blacklow, Michael J. Kruhlak, Junwei Shi, Jon C. Aster, Eric F. Joyce, Shawn C. Little, Golnaz Vahedi,,Warren S. Pear, and Robert B. Faryabi: Oncogenic Notch Promotes Long-Range RegulatoryInteractions within Hyperconnected D Cliques. Molecular Cell 73(6): 1174-1190, Mar 2019.
Steven E. Kirberger, Peter D. Ycas, Jorden A. Johnson, Chen Chen, Michael F. Ciccone, Rinette W. L. Woo, Andrew K. Urick, Huda Zahid, Ke Shi, Hideki Aihara, Sean D. McAllister, Mohammed Kashani-Sabet, Junwei Shi, Alex Dickson, Camila O. dos Santos and William C. K. Pomerantz: Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor. Org Biomol Chem 17(7): 2020-2027, Feb 2019.
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 10.1038/nbt.4194, Jan 2019 Notes: Epub ahead of print, Jul 2018.
Torre EA, Arai E, Bayatpour S, Beck LE, Emert BL, Shaffer SM, Mellis IA, Budinich KA, Weeraratna A, Shi J#, Raj A# #co-corresponding author: Genetic screening for single-cell variability modulators driving therapy resistance. BioRxiv 2019 Notes: preprint doi.org/10.1101/638809.
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 10;34(6): 970-981, Dec 2018.
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 15;7. pii: e41305., Nov 2018.
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# (# co-corresponding author): Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science Page: 361(6399):285-290, Jul 2018.