Junwei Shi, Ph.D.

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Assistant Professor of Cancer Biology
Department: Cancer Biology

Contact information
421 Curie Blvd., 610 BRB II/III
Philadelphia, PA 19104-6160
Office: 215-746-5733
Fax: 215-573-6725
Lab: 215-746-3614
B.S. (Biotechnology)
Sun Yat-sen University (China), 2008.
Ph.D. (Molecular and Cellular Biology)
Stony Brook University, SUNY, 2016.
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Description of Research Expertise

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.

Lab Members:

Diqiu Ren, Postdoctoral Researcher
Qingzhou Chen, Postdoctoral Researcher
Zhendong Cao, Graduate Student
Niklaus Evitt, Graduate Student
Chad Komar, Graduate Student
Kurtis McCannell, Graduate Student
Bianca Pingul, Graduate Student
Lizzie Freilich, Research Specialist
Deb Sneddon, Program Coordinator

Selected Publications

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, July 2020.

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* (*co-corresponding author): The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood(11;135(24)), 2121-2132, June 2020 Notes: doi: 10.1182/blood.2020005301.

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 10(6): 854-871, June 2020 Notes: doi: 10.1158/2159-8290.CD-19-1299. Epub 2020 Mar 18.

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* (*co-corresponding author): In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer. BioRxiv 2020 Notes: preprint link: https://www.biorxiv.org/content/10.1101/2020.05.20.087379v1

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 Page: 10(1):5151. doi: 10.1038/s41467-019-13086-5, Nov 2019.

Ehrenhöfer-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.

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Last updated: 08/24/2020
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