Project 2: Targeting Specific Lipid Species that Drive Ferroptosis Resistance

Project Summary Knowledge of the mechanisms that tumors use to subvert ferroptosis remains a gap. We discovered that breast and liver cancers use two lipids to prevent ferroptosis—coenzyme Q10 and oleic acid. Breast, liver, and other cancers upregulate key enzymes involved in producing the ferroptosis-blocking lipid coenzyme Q10. While CoQ10 functions in the mitochondrial electron transport chain, it also suppresses ferroptosis by blocking lipid peroxidation. Normalizing CoQ10 abundance enables ferroptosis to occur. In addition, the monounsaturated fatty acid (MUFA) oleic acid suppresses ferroptosis, once incorporated into phospholipids. We hypothesize that oleic acid competes with PUFAs for incorporation into phospholipids, reducing the concentration of PUFA-containing phospholipids in membranes. We propose to define how CoQ10 and oleic acid block ferroptosis in breast and hepatocellular (HCC) cancers using a variety of models and samples. These studies will provide new insights for restoring ferroptosis-mediated tumor suppression in specific cancer contexts, and provide a paradigm for understanding how cancers subvert ferroptosis. These studies will integrate with Projects 1 and 3 to answer three overarching questions: how does ferroptosis engage distinct PL species, how does cancer signaling regulate lipid-metabolism, and how does lipid-metabolism-mediated ferroptosis surveillance contribute to cancer progression and to treatment strategies.