Perelman School of Medicine at the University of Pennsylvania

Penn Institute for Immunology

Junwei Shi

faculty photo
Assistant Professor of Cancer Biology
Department: Cancer Biology
Graduate Group Affiliations

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
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.

Research Details:
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.

Lab Members:

Eri Arai, Research Specialist
Emily Duffner, Research Specialist
Rodrigo Gier, Research Specialist
Zhendong Cao, Graduate Researcher
Zhuoyu Wen, Undergraduate Researcher
Deb Sneddon, Administrative Coordinator

Selected Publications

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 Page: 32(13-14):915-928, Jul 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.

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: Epub ahead of print, Jul 2018.

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*(* co-corresponding author) : LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia. Molecular Cell. Molecular Cell, 10.1016/j.molcel.2018.02.011: online, Mar 2018.

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 Page: 9(1):782, Feb 2018.

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, De Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T.: Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552(7683): 126-131, Dec 2017.

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(2), e0172177, Feb 2017.

Anand S. Bhagwat, Jae-Seok Roe, Beverly Y.L. Mok, Anja F. Hohmann, Junwei Shi, Christopher R. Vakoc: BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements. Cell Reports 15(3): 1-12, April 2016.

Anja F. Hohmann, Laetitia J. Martin, Jessica Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnel, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, and Christopher R. Vakoc: Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nature Chemical Biology 2016.

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, May 2015.

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Last updated: 08/14/2018
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