Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer

Epithelial ovarian cancer is the fifth-leading cause of cancer-related death for women in North America and is responsible for over 100 000 deaths/year worldwide (Ferlay et al., 2015). High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype and the vast majority of women are diagnosed with advanced stage disease (Bowtell, 2010). The current standard treatment is aggressive surgery combined with adjuvant and/or neo-adjuvant platinum/taxane-based chemotherapy. Despite initial efficacy of standard therapy, resistant cancer recurs and 70% of patients die within 5 years after initial diagnosis (Bast et al., 2009). Further understanding of the molecular and cellular features that promote HGSC progression may assist in identifying new opportunities for therapeutic intervention and ultimately improve the prognosis of women with HGSC. My research has generated an extensive functional and genomic characterization of serous ovarian cancer cell lines and provides a framework for identifying vulnerabilities associated with distinct molecular features. Using this dataset, I have focused on the identification of genes encoding for highly expressed cell surface molecules. I have identified a novel role of the tetraspanin CD151 in serous ovarian cancer. I have found that CD151 depletion impairs survival, proliferation and tumor growth in murine models of a subset of HGSC cell lines. In search of the mechanism underlying CD151-dependency, I have uncovered a novel association for CD151-dependency in cancer cells with mesenchymal features. In particular, high ZEB1 and ZEB2 expression is tightly coupled with CD151-dependency and thus, may be used as biomarkers for stratifying tumors requiring CD151 for growth. Moreover, CD151-binding antibodies block the migratory capacity of CD151-dependent cells, thereby implicating CD151 in metastasis and dissemination of HGSC tumors. These studies provide a resource of characterized HGSC cell lines and suggest that CD151 may be a biological target in HGSC tumors.Ph.D