Adipocytes Protect Ovarian Cancer Cells from Ferroptosis

Ferroptosis is a regulated form of cell death driven by lipid oxidation. Induction of ferroptosis has emerged as a potential approach for cancer treatment. Work published by our group and others has suggested that ovarian cancer may be among the potential clinical targets of ferroptosis inducers. The microenvironment plays a key role in all ovarian cancers, including high-grade serous ovarian cancer (HGSOC). In particular, the adipocyte-rich omentum is an important metastatic niche for ovarian cancer peritoneal metastases. Given the pivotal role of adipocytes in the ovarian cancer microenvironment, in this work we sought to understand the contribution of adipocytes to ovarian cancer ferroptosis. We report that adipocytes and the adipocyte-conditioned medium (ACM) protect ovarian cancer cells from ferroptosis through a multifactorial process involving changes in membrane lipid composition and lipid sequestration. Inhibiting lipid transfer significantly enhanced the anti-tumor effect of erastin, a ferroptosis inducer, in immune-deficient mice bearing intraperitoneal ovarian tumors. Disabling this cytoprotective pathway may be key to the effective deployment of ferroptosis inducers in the treatment of ovarian cancer.