High grade serous cancer (HGSC) is the most common and malignant form of ovarian cancer with the highest incidence of mortality. Recent clinical and molecular studies strongly suggest that HGSC originates not from the ovary, but from the neighboring fallopian tube epithelia. While the discovery of an extra ovarian origin is a fundamental step toward improving detection and treatment, the absence of relevant, human models has hindered our understanding of the initiation and progression of HGSC. Inherited genetic mutation in breast cancer gene 1 (BRCA1) is known as highest risk factor for HGSC development. In this study, we aim to investigate early genomic alterations and disease progression seen in patients with a BRCA1 mutation using an induced pluripotent stem cell (iPSC) technology-based disease model.
Toward this goal, we recently developed an iPSC derived 3D model of human fallopian tube epithelium (FTE) which recapitulates the tissue architecture and appropriate functional cells of the fallopian tube. Furthermore, we generated three different BRCA1 mutant iPSC cell lines from patients with early onset of cancer. In the proposed project, we will investigate the hormonal, mechanical and genomic mechanisms that contribute to neoplastic transformation of FTE with a BRCA1 mutation. Since our FTE model provides the opportunity to study the cell and its interaction with its microenvironment, we will also explore the role of the stromal microenvironment on cancer progression. We propose that the iPSC-derived FTE model provides a more faithful and thus improved human cell model to explore early cancer pathogenesis within a tumor microenvironment. This project is made feasible by the unique combination of the Regenerative Medicine Institute and gynecological oncologists at Cedars-Sinai, we have the potential to yield novel insights into ovarian cancer pathogenesis and thus make head way into developing more effective treatments for ovarian cancer.