Rugang Zhang

faculty photo
Department: Genetics
Graduate Group Affiliations

Contact information
The Wistar Institute
3601 Spruce Street
Room 333
Philadelphia, PA 19104
Office: 215-495-6840
Education:
B.Sc.
Anhui Normal University, Anhui, China, 1997.
Ph.D.
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China, 2002.
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Description of Research Expertise

Research Interests:

To understand the basic mechanisms underlying cellular senescence, an important process in both tissue aging and cancer.

To identify novel intervention strategies for epithelial ovarian cancer (EOC), the most lethal gynecological malignancy in the developed world.

Key Words:

Epithelial Ovarian Cancer, Epigenetic Cancer Therapy, Targeted Cancer Therapy Resistance, Combination Therapy, PARP Inhibitor, DNA Repair Pathway, Immunological Vulnerability, EZH2, SWI/SNF, ARID1A, ER Stress Response, Cellular Senescence, Senescence-Associated Secretory Phenotype, Tumor Suppression, Chromatin Structure, Cancer Metabolism, 3D Genome Structure

Research Details:

It is well known that cancer is a disease caused by oncogene activation and inactivation of tumor suppressor genes. Paradoxically, activation of oncogenes or inactivation of tumor suppressor genes alone in primary mammalian cells often triggers a state of stable cell growth arrest, known as cellular senescence. Overcoming the senescence-associated cell growth arrest is a necessary step during cell transformation. It is therefore critical to understand the mechanistic basis of oncogenic signaling in the context of senescence induction and bypass. This biological process represents an ideal paradigm to examine the role of DNA damage response, epigenetically determined chromatin structure, and metabolic reprogramming during cancer initiation and progression.

A major discovery in recent cancer genome-wide sequencing is the identification of significant genetic changes in chromatin-modifying genes. However, despite great strides in identifying the various epigenetic enzymes/factors involved in cancer, the translational application of these findings in cancer intervention remains to be explored. Zhang lab will pursue these issues in the coming years by focusing on the epigenetic SWI/SNF and PRC2 complexes as proof of principles in the context of epithelial ovarian cancer.

Zhang lab will continue to use its strengths in biochemical, molecular and cellular cancer biology to decipher the mechanistic basis of cancer. Simultaneously, the lab will increase its focus on the utilization of model organisms, including genetic mouse models, and carefully chosen clinically relevant pre-clinical cancer models to explore the translational application of the mechanistic findings. His laboratory primarily focuses on ovarian cancer, which ranks first as the cause of death for gynecological cancers in the developed world.

Rotation Projects for 2020-2022

1. Chromatin basis of senescence-associated secretory phenotype.
2. Targeting senescence-associated metabolic vulnerability to develop cancer therapeutics.
3. Targeting senescence-associated immunological vulnerability to develop cancer therapeutics.
4. Epigenetic approaches to therapy resistance in ovarian cancer.
5. Epigenetic approaches to immunological therapeutic targets in ovarian cancer.
6. Developing mechanism guided therapeutic strategies for loss of function mutations in the SWI/SNF complex subunits such as ARID1A in ovarian cancer.
7. PARP inhibitors resistance mechanism in "BRCAness" ovarian cancer.
8. Expanding the utility of PARP inhibitors into homologous recombination proficient ovarian cancer.

Lab personnel:

Current:

Sergey Karakashev, Ph.D., Postdoctoral Associate (Supported by AACR-AstraZeneca Postdoctoral Fellowship and NIH/NCI K99/R00 Award)
Shuai Wu, Ph.D., Postdoctoral Associate (Supported by OCRA Ann Schreiber Mentored Investigator Award)
Pingyu Liu, Ph.D., Postdoctoral Associate
Bo Zhao, Ph.D., Postdoctoral Associate
Jianhuang Lin, Ph.D., Postdoctoral Associate (Supported by OCRA Ann Schreiber Mentored Investigator Award)
Xue Hao, Ph.D., Postdoctoral Associate
Wei Zhou, Ph.D, Postdoctoral Associate
Heng Liu, Ph.D., Postdoctoral Associate
Joseph Zundell, B.S., Predoctoral Student (Supported by NIH/NCI F31 Award)
Zhongping Dai, M.S.

Alumni

Postdocs:

Zhigang Tu, Ph.D., 2008 - 2013 Currently Professor in Jiangsu University, China
Hua Li, M.D., Ph.D., 2009 - 2014
Michael Amatangelo, Ph.D., 2012 - 2013 (supported by NIH/NCT T32 grant) Currently Senior Scientist at Celgene
Benjamin Bitler, Ph.D., 2010 - 2016 (Supported by ACS Postdoctoral Fellowship and NIH/NCI K99/R00 Award) Currently Assistant Professor at University of Colorado
Katherine Aird, Ph.D., 2010 - 2016 (Supported by NIH/NCI T32 grant and K99/R00 Award) Currently Assistant Professor at Penn State University
Hengrui Zhu, Ph.D., 2013 - 2017 (Supported by OCRA Ann Schreiber Mentored Investigator Award) Currently Senior Scientist at Johnson & Johnson
Yuki Yokoyama, Ph.D., 2014 - 2016 Currently Assistant Professor at Osaka University, Japan
Fee Bengsch, Ph.D., 2014 - 2015 Currently Industry Back to Germany
Takeshi Fukumoto, M.D., Ph.D., 2016 - 2019 Currently Assistant Professor at Kobe University, Japan
Timothy Nacarelli, Ph.D., 2016 - 2019 Currently Investigator at GSK

Graduate Students

Azat Garipov, B.S., 2010 - 2014 Currently Senior Medical Advisor, BIOCAD

Selected Publications

Karakashev S, Fukumoto T, Zhao B, Lin J, Wu S, Fatkhutdinov N, Park PW, Semenova G, Jean S, Gadungog MG, Borowsky ME, Kossenkov AV, Liu Q, Zhang R: EZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibition. Cancer Cell In Press.

Zhao B, Liu P, Fukumoto T, Nacarelli T, Fatkhutdinov N, Wu S, Lin J, Aird KM, Tang SY, Liu Q, Speicher DW, Zhang R: Topoisomerase 1 cleavage complex enables pattern recongnition and inflammation during senescence. Nature Communications In Press.

Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, Noma K, Baur JA, Schug Z, Tang HY, Speicher DW, David G, Zhang R: NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature Cell Biology 21: 397-407, 2019.

Zhao B, Lin J, Rong L, Wu S, Deng Z, Fatkhutdinov N, Zundell J, Fukumoto T, Liu Q, Kossenkov A, Jean S, Cadungog MG, Borowsky ME, Drapkin R, Lieberman PM, Abate-Shen CT, Zhang R: ARID1A promotes genomic stability through protecting telomere cohesion. Nature Communications 10: 4067, 2019.

Wu S, Fatkhutdinov N, Rosin L, Luppino JM, Iwasaki O, Tanizawa H, Tang HY, Kossenkov AV, Gardini A, Noma KI, Speicher DW, Joyce EF, Zhang R: ARID1A spatially partitions interphase chromosomes. Science Advances 5: eaaw5294, 2019.

Wu S, Fatkhutdinov N, Fukumoto T, Bitler BG, Park PH, Kossenkov AV, Trizzino M, Tang HY, Zhang L, Gardini A, Speicher DW, Zhang R: SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells. Nature Communications 9: 4116, 2018.

Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, Lee JH, Kossenkov AV, Gaonkar KS, Yan H, Drapkin R, Conejo-Garcia JR, Speicher DW, Ordog T, Zhang R: CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nature Communications 9: 631, 2018.

Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, Zhai Y, Kossenkov AV, Vara-Ailor A, Rauscher FJ III, Zou W, Speicher DW, Huntsman DG, Conejo-Garcia JR, Cho KR, Christianson DW, Zhang R.: ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nature Cell Biology 19(8): 962-973, 2017.

Bitler BG, Garipov A, Amatangelo M, Kossenkov A, Schultz DC, Shih IM, Conejo-Garcia JR, Speicher DW, Zhang R. : Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nature Medicine 21(3): 231-238, 2015.

Tu, Z., Aird, K. M., Bitler, B. G., Nicodemus, J. P., Beeharry, N., Xia, B., Yen, T. J., Zhang, R.: Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Developmental Cell 21(6): 1077-91, 2011.

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Last updated: 10/07/2020
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