Abstract B032: Investigating the role of progesterone in the metastasis of high-grade serous ovarian cancer

Abstract Ovarian cancer is the fifth leading cause of cancer-related death among women and has the highest mortality rate among gynecologic malignancies. High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal subtype, accounting for approximately 70% of ovarian cancer related deaths. Increasing evidence supports the fallopian tube epithelium (not the ovarian surface epithelium) as the site of origin for HGSOC. The migration of tumorigenic fallopian tube epithelial cells to the ovary and peritoneal surfaces may be influenced by local metabolites and signaling molecules within the tumor microenvironment. While certain metabolites may promote tumorigenesis, others could exert protective effects. In collaboration with the University of California, Santa Cruz, and utilizing Imaging Mass Spectrometry (IMS), we examined the metabolic profile of co-cultures using tumorigenic murine oviductal epithelial (MOE) cells harboring PTEN knockdown (MOE PTENshRNA) and murine ovarian tissue explants. Among the differentially expressed metabolites, progesterone was identified to be significantly increased when tumorigenic cells were in proximity with a murine ovary. Notably, similar metabolite changes were not observed in non-tumorigenic MOE cells or in models derived from ovarian surface epithelium, emphasizing the specificity of progesterone signaling in this fallopian tube-derived model. Progesterone is a key steroid hormone in female reproductive physiology and has been associated with a reduced risk of developing HGSOC, particularly in the context of parity and progestin-based oral contraceptive use. MOE PTENshRNA cells endogenously express progesterone receptor isoforms (PR-A and PR-B), and we observed elevated PR expression in these cells relative to non-tumorigenic controls via Western blot analysis. Functionally, we found that treatment with 200 nM progesterone inhibited cell migration in MOE PTENshRNA cells. However, this inhibitory effect was not observed in cells that also expressed additional oncogenic drivers such as KRASG12V and mutant p53R273H, suggesting that the protective effect of progesterone may be circumvented by downstream oncogenic mutations. Although we did not see any changes in proliferation, and subtle changes in transcript expression following RNAseq analysis, these findings highlight the value of this fallopian tube derived tumorigenic model system in studying HGSOC and underscore the potential role of progesterone as a modulator of tumor cell behavior. While the underlying mechanisms remain to be elucidated, our study provides a critical foundation for investigating hormone-mediated regulation of cell migration and its implications for ovarian cancer metastasis. Citation Format: Diandra M. Vaval Taylor, Jason Guerrero, Katherine Schoenhardt, Laura M. Sanchez, Joanna E. Burdette. Investigating the role of progesterone in the metastasis of high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B032.