Lipid Metabolism as a Determinant of Ferroptosis Sensitivity in Cancer

Project Summary Ferroptosis, a cell death process driven by iron-dependent phospholipid (PL) peroxidation, has emerged as an active research field with its publication number doubling annually since the concept was introduced and the term was coined by Dr. Stockwell in 2012. Ferroptosis plays a crucial role in various diseases. In cancer biology, ferroptosis has been implicated as an endogenous tumor suppressive mechanism and its induction is being explored as a uniquely effective therapeutic approach for aggressive, drug-resistant cancers. Remarkably, cellular metabolism, particularly lipid metabolism, plays a central role in the execution of, surveillance of, and evasion from, ferroptosis. In this program, three highly integrated projects seek to determine the roles, regulation, and underlying mechanisms of lipid metabolism in ferroptosis and to explore novel cancer therapeutic approaches based on the elucidated mechanisms. Project 1, “Phospholipid remodeling in ferroptosis and cancer”, led by Dr. Xuejun Jiang (Memorial Sloan Kettering Cancer Institute), investigates how multiple phospholipid-modifying enzymes dictate ferroptosis sensitivity through specifically rewiring cellular phospholipid profiles and how these events are regulated by cancer signaling. Project 2, led by Dr. Brent Stockwell (Columbia University), "Targeting specific lipid species that drive ferroptosis resistance", centers on roles and biogenesis of two specific lipids in driving resistance of cancer cells to ferroptosis. Project 3, “PHLDA2–mediated phospholipid oxidation in ferroptosis and tumor suppression”, led by Dr. Wei Gu (Columbia University Medical Center), explores a unique and noncanonical phospholipid peroxidation process that drives ferroptosis in some cancers. One Shared Resource Core (SR Core) (Leader: Dr. Brent Stockwell, “Ferroptosis biomarkers and lipidomic analysis”) will support all these projects by performing essential lipidomic and ferroptosis biomarker analysis in cellular models and in vivo models. The proposed projects are based on extensive and collaborative preliminary studies; in all three projects, novel cancer therapeutic approaches based on the elucidated mechanisms will be tested by using genetically engineered and xenograft mouse models, including patient- derived xenograft (PDX) models with clinically relevant genetic backgrounds. Overall, the proposed program will define key mechanisms by which cancers modulate ferroptosis through lipid metabolism and will provide novel approaches for the development of ferroptosis-induction-based cancer therapeutic strategies for targeting aggressive malignancies, with a special focus on breast and liver cancers.