Defining the role of progesterone signaling in high grade serous ovarian cancer using fallopian tube models

High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal subtype of ovarian cancer, 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. 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 PTENshRNA). 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 PTENshRNA cells. RNA sequencing further revealed that progesterone treatment led to the downregulation of key angiogenesis markers in MOE PTENshRNA cells. 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.