Uncovering the Mechanisms of Metastasis in Fallopian Tube-Originated Ovarian Cancer

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The vast majority of ovarian cancer patients die from metastatic disease due to lack of effective treatments. To more successfully treat these women, we urgently need to better understand the molecular mechanisms of ovarian cancer metastasis. Up to 70% of ovarian cancers are high-grade serous carcinomas (HGSC). These cancers most commonly initiate from secretory epithelial cells in the fallopian tube (FT) and are highly metastatic. Genetic alterations, including BRCA and p53 mutations, facilitate the transformation of FT cells into serous tubal intraepithelial carcinomas as the precursor lesions of HGSCs. Cells then spread throughout the peritoneal cavity even before the clinically manifested “primary” ovarian tumors are detected, thus only 15% of patients are diagnosed with more- curable stage I disease. Very little is known about the molecular and cellular process driving the formation of disseminated intraperitoneal tumors. Our Ovgp1-iCreER BPRN mouse model recapitulates the development of precursor lesions from oviduct (equivalent of human FT) and forms metastatic HGSC, allowing us to explore the process of metastatic tumor development in HGSC. We carried out single-cell RNA-sequencing of oviducts and tumors from the BPRN mice and identified a population of tumor-initiating cells (TICs) with an increased ability to produce tumor organoids in vitro and form metastases in vivo. We validated their presence in human HGSC samples and found their gene signature to be enriched in 40% of HGSC patient samples in TCGA dataset and associated with poor prognosis. Using single-cell regulatory networks analysis, we determined that the nuclear receptor subfamily 2 group F member 2 (NR2F2) pathway was activated in these TICs. On the basis of our preliminary data and prior research, we hypothesize that NR2F2 pathway is critical for the FT-originated TICs to drive metastasis in HGSC. We propose three aims to test our hypothesis: 1) Define the molecular mechanism by which NR2F2 regulates migration and adhesion of ovarian cancer cells; 2) Characterize the expression and activation pattern of NR2F2 at different stages of tumor development in the BPRN mouse model. 3) Determine the biological and mechanistic effects of NR2F2 inhibition on metastasis of HGSC. The proposed study will provide novel insights into mechanisms of HGSC metastasis and inform the development of new strategies for inhibiting metastasis and prevent their recurrence in women with HGSC.