Sharon Cantor, Ph.D.

BIOGRAPHICAL SKETCH:

Sharon Cantor is a Professor and Gladys Smith Martin Chair in Oncology in the Department of Molecular, Cell and Cancer Biology at the University of Massachusetts Chan Medical School. She is also Associate Director of Basic Research of the UMASS Cancer Center.

Following her undergraduate studies at University of Michigan, where she received a B.S. in Biology and played division one field hockey, she received her Ph.D. in Biochemistry from Tufts University. She continued her training as a Postdoctoral Fellow in the Dana Farber Cancer Institute and Harvard Medical School.

In 2001, she became an instructor in medicine at Harvard Medical School until 2003 when she became an Assistant Professor at the University of Massachusetts Chan Medical School. She was the Director of Cancer Biology Graduate Program from 2010 to 2018 and became the Associate Director for Basic Research of the Cancer Center in 2021.

Dr. Cantor is a recipient of several awards including the Dean’s Award for Outstanding Contribution to Graduate Education and recently elected as the Chair of the GRC, “DNA Damage, Mutation and Cancer.

Her research is currently supported by three grants from the National Cancer Institute and a Fanconi Anemia Research Fund grant.

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research

My research impacts how we understand and treat cancer. For decades it was thought that chemotherapies caused DNA double-strand breaks (DSBs), which were lethal when not effectively repaired as in hereditary breast and ovarian cancer (HBOC) with mutations in the BRCA1 or BRCA2 (BRCA) genes. However, this hypothesis did not explain the many tumors that fail to respond to chemotherapy. We uncovered that BRCA-mutant cancer cells have another defect: the inability to suppress DNA replication gaps, findings supported by several groups working in diverse cell systems. We further sought to identify and found that these gaps become a liability because they are exacerbated by chemotherapy, which also induces gaps including PARP inhibitors (PARPi) (Nayak et al., Science Advances, 2020, Panzarino et al., Cancer Res 2021, Cong et al., Molecular Cell 2021). Correspondingly, genes whose loss suppresses gaps accurately predict poor response in patients with BRCA2 mutant ovarian cancer whereas genes whose loss restores DNA repair or prevent DSBs by fork protection had no predictive value (Panzarino et al., Cancer Res 2021). Moreover, we found that to combat chemoresistance, it is essential to target gap suppression that is mediated by several mechanisms including translesion synthesis (TLS). Consistent with TLS being an adaptive response in cancer, targeting TLS is effective in blocking cancer growth without affecting non-cancer cells (Nayak et al., Sci Adv 2020). Gap suppression also aligns with PARPi resistance in BRCA1-mutant cells with 53BP1 deficiency, a mechanism of resistance previously linked to restored DSB repair. We found that BRCA1-mutant cells have a lagging strand defect that is corrected by loss of 53BP1 (Cong et al., Molecular Cell 2021). Moreover, re-sensitization of these cells restores gaps, not DSBs (Dias et., Molecular Cell 2021). Collectively, our work redirects the essential function of HBOC genes from DSB repair to gap suppression, which, when compromised, renders tumors sensitive to therapy. We therefore redefine the concept of “BRCAness,” from defective DSB repair to replication gaps. This rethinking has considerable implications for biomarkers and therapy design. Rather than DSB repair deficiency, our research demonstrates that gaps are a more precise and clinically significant biomarker. Moreover, effective drug combinations should be designed to maximize gaps and target gap suppression (Cantor, DNA Repair 2021 and Cong and Cantor, Molecular Cell, in press).

Groundwork for these studies began with the cloning of the third HBOC gene, FANCJ/BACH1/BRIP1) (Cantor et al., Cell 2001). Subsequently, we linked FANCJ to the cancer-prone disease Fanconi anemia (FA) that also includes developmental defects (Litman et al., Cancer Cell 2005). We found that FANCJ functions in DNA replication (Peng et al., Cell Reports 2018), a role that could explain the seemingly paradoxical roles in tumor suppression and proliferation. Studies on FANCJ also provided insight to chemoresistance. The direct interaction between FANCJ and BRCA1 was required for DNA repair, but, unexpectedly, loss of the interaction did not sensitize cells to drugs such as cisplatin. We found resistance was mediated by TLS (Xie et al., Oncogene 2010) that is regulated by acetylation (Xie et al Plos Gen. 2012) and coordinated with mismatch repair (Xie et al., Cancer Prevention Research 2010). TLS confers chemoresistance in BRCA2 mutant cancer cells (Guillemette et al., Gene and Dev. 2015) a finding initially overshadowed by fork protection (Chaudhuri et al., Nature 2016) that we now uncouple from resistance (Panzarino et al Cancer Res 2020). Given that replication gaps underlie BRCA-mutant cancer, a major implication is that gaps also cause FA and that countering them will improve patient health. Henceforth our work seeks to identify tools to both induce and suppress gaps.

Click here for a complete list of published work

Rotation Projects

The laboratory is interested in a range of DNA replication/repair-related topics including (i) Defining biomarkers of “BRCAness” that signifies deficiency in the hereditary breast/ovarian cancer genes, BRCA1 or BRCA2, (ii) Targeting BRCAness as a replication gap vulnerability, (iii) Defining why replication proficiency requires the FANCJ helicase disengage mismatch repair proteins, (iv) Determining if suppressing gaps improves the health of Fanconi anemia patient cells, (v) Hunting down the cancer vulnerability that defines curability, (vi) performing functional genomic screens to uncover mechanisms regulating chemotherapy resistance.

Positions available  

A post-doctoral, technician, and graduate laboratory rotational positions are available. Email Sharon Cantor