Versican secreted by the ovary links ovulation and migration in fallopian tube derived serous cancer

Abstract

High grade serous ovarian cancers (HGSOC) predominantly arise in the fallopian tube epithelium (FTE) and colonize the ovary first, before further metastasis to the peritoneum. Ovarian cancer risk is directly related to the number of ovulations, suggesting that the ovary may secrete specific factors that act as chemoattractants for fallopian tube derived tumor cells during ovulation. We found that 3D ovarian organ culture produced a secreted factor that enhanced the migration of FTE non-tumorigenic cells as well as cells harboring specific pathway modifications commonly found in high grade serous cancers. Through size fractionation and a small molecule inhibitors screen, the secreted protein was determined to be 50–100kDa in size and acted through the Epidermal Growth Factor Receptor (EGFR). To correlate the candidates with ovulation, the PREDICT organ-on-chip system was optimized to support ovulation in a perfused microfluidic platform. Versican was found in the correct molecular weight range, contained EGF-like domains, and correlated with ovulation in the PREDICT system. Exogenous versican increased migration, invasion, and enhanced adhesion of both murine and human FTE cells to the ovary in an EGFR-dependent manner. The identification of a protein secreted during ovulation that impacts the ability of FTE cells to colonize the ovary provides new insights into the development of strategies for limiting primary ovarian metastasis.