Lab In The News
Wistar Scientists Identify Novel Therapeutic Approach to Re-activate Immune Response Against Tumors
PHILADELPHIA — (June 21, 2022) — Due to the development of resistance to chemotherapy and recurring tumors, patients with ovarian cancer often have low survival rates. Therefore, new therapeutic options such as targeted therapy that boosts anti-tumor immunity are needed to improve ovarian cancer...
Wistar Scientists Reveal New Function of Enzyme ADAR1 Linking it to Age-Related Diseases via a Role Independent of RNA-editing During AgingResearchers found that the downregulation of enzyme ADAR1 promotes senescence and is associated with age-related neurodegeneration.
The Zhang Laboratory
The Zhang laboratory studies ovarian cancer biology with the goal of developing novel therapeutic approaches to combat the disease with precision. In particular, the lab investigates how alterations in epigenetics— or the heritable changes that affects gene expression without alterations in the underlying DNA sequence—contribute to epithelial ovarian cancer. The ultimate goal of this line of investigation is to leverage these newly gained mechanistic insights for developing new therapeutics in a personalized manner based on one’s unique genetic and/or pathway signatures.
The Zhang laboratory also investigates the mechanisms that underlie aging in normal mammalian cells and how this process is implicated in tissue aging or evaded by tumor cells during malignant transformation. In particular, the lab focuses on epigenetic and metabolic pathways that regulate the aging process. The overarching goal for identifying such mechanisms is the development of novel strategies to promote healthy aging and combat cancer.
Dajiang Guo, Ph.D.
Xue Hao, Ph.D.
Sergey Karakashev, Ph.D. (AACR-AstraZeneca Fellowship and NIH/NCI K99/R00 Pathway to Independence Award)
Jianhuang Lin, Ph.D. (OCRA Ann Schreiber Mentored Investigator)
Heng Liu, Ph.D.
Hao Nie, Ph.D.
Chen Wang, Ph.D.
Shuai Wu, Ph.D. (OCRA Ann Schreiber Mentored Investigator)
Wei Zhou, Ph.D.
Renyta Moses (CAMB/CB Rotation Ph.D. Student)
Joseph Zundell (NIH/NCI F31 Predoctoral Fellowship)
Zhigang Tu, Ph.D. (2008 – 2013) Professor, Jiangsu University, China
Hua Li, M.D., Ph.D. (2009 – 2014)
Michael Amatangelo, Ph.D. (2012 – 2013) Senior Scientist, Celgene (NIH/NCI T32 and F32 Postdoctoral Fellowship)
Katherine Aird, Ph.D. (2010 – 2016) Assistant Professor, Penn State University (NIH/NCI T32 Postdoctoral Fellowship and K99/R00 Pathway to Independence Award)
Benjamin G. Bitler, Ph.D. (2010 – 2016) Assistant Professor, University of Colorado (ACS Postdoctoral Fellowship and NIH/NCI K99/R00 Pathway to Independence Award)
Hengrui Zhu, Ph.D. (2013 – 2017) Senior Scientist at Johnson & Johnson (OCRA Ann Schreiber Mentored Investigator)
Yuki Yokoyama, Ph.D. (2014 – 2016) Assistant Professor, Osaka University, Japan
Fee Bengsch, Ph.D. (2014 – 2015) Industry, Germany
Takeshi Fukumoto, M.D., Ph.D. (2016 – 2019) Assistant Professor, Kobe University, Japan
Timothy Nacarelli, Ph.D. (2016 – 2019) Investigator, GSK(NIH/NCI T32 Postdoctoral Fellowship)
Bo Zhao, Ph.D. (2017 -2020) Principal Investigator, Kunming Institute of Zoology, Chinese Academy of Sciences, China
Pingyu Liu, Ph.D. (2017 -2021) Principal Investigator, Tongji University, Shanghai, China
Azat Garipov (2010 – 2014) Senior Medical Advisor, BIOCAD, Russia
Motivated candidates are encouraged to inquire about the positions below. Contact firstname.lastname@example.org.
Epigenetics of epithelial ovarian cancer
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. The Zhang lab will pursue these issues in the coming years by focusing on the epigenetic SWItch/Sucrose Non-Fermentable (SWI/SNF) and Polycomb repressive complex 2 (PRC2) complexes as proof of principles in the context of ovarian cancer.
a. Mechanism-guided therapeutic strategies for genetic alterations that affect the SWI/SNF chromatin remodeling complex in epithelial ovarian cancer (such as ARID1A mutation in clear cell and endometrioid subtypes of ovarian cancer, and CARM1 amplification/overexpression in high-grade serous ovarian cancer).
b. Epigenetic approaches to chemotherapy resistance and cancer stemness in epithelial ovarian cancer.
c. Epigenetic approaches to primer for and/or synergize with immunological therapy in epithelial ovarian cancer.
d. PARP inhibitors resistance mechanism and approaches to sensitizing BRCA-proficient ovarian cancer to PARP inhibitors.
Epigenetic and metabolic basis of cellular senescence
Cellular senescence is a state of stable cell growth arrest that is accompanied by drastic molecular and phenotypic changes. Cellular senescence is a major contributor to tissue aging and plays a context-dependent role in tumor development. For example, cellular senescence is tumor suppressive and overcoming the senescence-associated cell growth arrest is a necessary step during cell transformation. In contrast to its tumor suppressive function, senescent cells can also promote cancer by acquiring a secretory phenotype and create a pro-tumorigenic microenvironment. The biological process of cellular senescence represents an ideal paradigm to examine the role of the DNA damage response, epigenetically determined chromatin structure, and metabolic reprogramming during tissue aging and cancer development.
a. Chromatin basis of the senescence-associated secretory phenotype.
b. Targeting senescence-associated metabolic vulnerability to develop cancer therapeutics.
c. Targeting senescence-associated immunological vulnerability to develop cancer therapeutics.
Liu, P., Li, F., Lin, J., Fukumoto, T., Nacarelli, T., Hao, X., Kossenkov, A.V., Simon, M.C., Zhang, R. “m 6 A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.” Nat Cell Biol. 2021 Apr;23(4):355-365. doi: 10.1038/s41556-021-00656-3. Epub 2021 Apr 1.
Wu, S., Fukumoto, T., Lin, J., Nacarelli, T., Wang, Y., Ong, D., Liu, H., Fatkhutdinov, N., Zundell, J.A., Karakashev, S., Zhou, W., Schwartz, L.E., Tang, H., Drapkin, R., Liu, Q., Huntsman, D.G., Kossenkov, A.V., Speicher, D.W., Schug, Z.T., Dang, C.V., Zhang, R. “Targeting Glutamine Dependence Through GLS1 Inhibition Suppresses ARID1A-inactivated Clear Cell Ovarian Carcinoma”. Nature Cancer (2021). Epub 2021 Jan 11
Karakashev, S., Fukumoto, T., Zhao, B., Lin, J., Wu, S., Fatkhutdinov, N., Park, P.H., Semenova, G., Jean, S., Cadungog, M.G., Borowsky, M.E., Kossenkov, A.V., Liu, Q., Zhang, R. “EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.” Cancer Cell. 2020 Feb 10;37(2):157-167.e6. doi: 10.1016/j.ccell.2019.12.015. Epub 2020 Jan 30.
Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K.M., Iwasaki, O., Kossenkov, A.V., Schultz, D., et al. “NAD+ metabolism governs the proinflammatory senescence-associated secretome.” Nature Cell Biology. 2019 Mar;21(3):397-407. doi: 10.1038/s41556-019-0287-4. Epub 2019 Feb 18.
Biter, B.G., Aird, K.M., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A.V., Schultz, D.C., Liu, Q., Shih, I.M., Conejo-Garcia, J.R., Speicher, D.W., Zhang, R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015 Mar;21(3):231-8. doi: 10.1038/nm.3799. Epub 2015 Feb 16.