Lab In The News
Novel Role in Spatial Chromosome Organization Identified for Frequently Mutated Cancer Protein
ARID1A controls how the genome is spatially organized in the nucleus to coordinate gene expression.
New Insight Into the Balance Between the Tumor-suppressive and Tumor-promoting Effects of Cellular Senescence
Increased NAD+ metabolism promotes cancer progression in a preclinical model of pancreatic cancer through increased secretion of senescence-associated proinflammatory molecules.
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.
Takeshi Fukumoto, M.D., Ph.D.
Sergey Karakashev, Ph.D.
Jianhuang Lin, Ph.D.
Pingyu Liu, Ph.D.
Timothy Nacarelli, Ph.D.
Galina Semenova, M.D., Ph.D.
Shuai Wu, Ph.D.
Bo Zhao, Ph.D.
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.
Nacarelli, T., Lau, L., Zhang, R., et al. "NAD+ metabolism governs the proinflammatory senescence-associated secretome." Nature Cell Biology. in press.
Karakashev, S., Zhu, H., Zhang, R., et al. " CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity." Nat Commun. 2018 Feb 12;9(1):631. doi: 10.1038/s41467-018-03031-3.
Bitler, B.G., Wu, S., Zhang, R., et al. "ARID1A-mutated ovarian cancers depend on HDAC6 activity." Nat Cell Biol. 2017 Aug;19(8):962-973. doi: 10.1038/ncb3582. Epub 2017 Jul 24.
Zhu, H., Bengsch, F., Zhang R., et al. "BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression." Cell Rep. 2016 Sep 13;16(11):2829-2837. doi: 10.1016/j.celrep.2016.08.032.
Bitler, B.G., Aird, K.M., Zhang, R., et al. "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.