Netrin signaling mediates survival of dormant epithelial ovarian cancer cells

Abstract

AbstractDormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We utilized a suspension culture model of high grade serous ovarian cancer (HGSOC) cell dormancy and devised a novel CRISPR screening approach to identify genetic requirements for cell survival under growth arrested and spheroid culture conditions. In addition, multiple RNA-seq comparisons were used to identify genes whose expression correlates with survival in dormancy. Combined, these approaches discover the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1 and -3, UNC5H receptors, DCC and other fibronectin receptors induce low level ERK activation to promote survival in dormant conditions. Furthermore, we determine that Netrin-1 and -3 overexpression is associated with poor prognosis in HGSOC and demonstrate their overexpression elevates cell survival in dormant conditions. Lastly, Netrin-1 or -3 overexpression contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.