TMET-37. TARGETING LIPID MEDIATED NON-CANONICAL CELL DEATH IN MALIGNANT GLIOMA

Abstract Resistance to canonical cell death mechanisms (e.g. apoptosis) is a hallmark of glioma and consequently driving the dismal outcomes of patients with glioma. Recent work has demonstrated gliomas are susceptible to non-apoptotic forms of cell death mediated by rewired lipid metabolism. Here we explored whether gliomas are vulnerable to other lipid-dependent forms of cell death. Our investigation revealed a large subset of patient-derived glioma cells that are exquisitely sensitive to a novel cell death pathway dependent on palmitate. Intriguingly, sensitivity to this type of cell death was linked to glioma tumor cells having a proneural identity and a specific enrichment in sphingolipid metabolic features. The catabolism of glioma sphingolipids established palmitate pools for protein S-palmitoylation, a necessary requirement to trigger palmitate mediated cell death in glioma, which was coupled to the exclusive expression of palmitoyl acyltransferases unique to proneural glioma tumors. Ongoing efforts aim to explore the mechanistic link between glioma identity, lipotype and susceptibility to palmitate dependent lethality. Taken together, these results identify a new approach to drive glioma cell death by targeting non-canonical cell death mediated by rewired glioma lipid metabolism.