Defining the Role of Progesterone Signaling in High-Grade Serous Ovarian Cancer Using Fallopian Tube Models

Background Ovarian cancer is the sixth leading cause of cancer-related deaths 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. Results Utilizing mass spectrometry imaging (MSI), we examined the metabolic profile of co-cultures using murine ovaries and tumorigenic murine oviductal epithelial (MOE) cells harboring PTEN knockdown (MOE PTEN ^shRNA ). Among the differentially expressed metabolites, progesterone was identified to be significantly increased when tumorigenic cells were in proximity with a murine ovary. In parallel, progesterone significantly reduced the adhesion of tumorigenic cells to the murine ovary. Functionally, treatment with 100nM progesterone inhibited the migration of MOE PTEN ^shRNA cells. However, this inhibitory effect was not observed in cells harboring additional oncogenic drivers, such as mutant p53 (p53 ^R273H ). RNA sequencing further revealed that progesterone treatment led to the downregulation of key angiogenesis markers in MOE PTEN ^shRNA cells. Notably, while combination treatment with progesterone and Olaparib did not alter cellular proliferation, higher concentrations of progesterone were associated with decreased expression of cancer stem cell-like markers. Conclusion These findings highlight the value of utilizing fallopian tube derived tumorigenic model systems in studying HGSOC and underscore the potential role of progesterone as a modulator of tumor cell behavior. Our study provides a critical foundation for investigating hormone-mediated regulation of cell migration and its implications for ovarian cancer metastasis.