DDR2 Confers Ferroptosis Resistance to Cancer-Associated Fibroblasts and Attenuates PARPi Sensitivity of Ovarian Tumor Cells

Abstract In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide–triggered form of cell death, is one such pathway. Cancer-associated fibroblasts (CAF) are key stromal cells in the ovarian tumor microenvironment that can affect therapeutic responses. Using various genetic approaches, we generated multiple DDR2-expressing and DDR2-deficient human ovarian tumor and mouse breast tumor CAFs. We found that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT–GSH–GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through noncanonical p62-dependent NRF2 activation and the labile iron pool by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against olaparib-induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we found that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could affect therapeutic sensitivity and resistance to PARPi. Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to ovarian tumor cells by protecting CAFs from ferroptosis.