CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis

Cancer Cell. 2023 Jun 12;41(6):1048-1060.e9. doi: 10.1016/j.ccell.2023.05.001. Epub 2023 May 25.

Abstract

Malignant tumors exhibit heterogeneous metabolic reprogramming, hindering the identification of translatable vulnerabilities for metabolism-targeted therapy. How molecular alterations in tumors promote metabolic diversity and distinct targetable dependencies remains poorly defined. Here we create a resource consisting of lipidomic, transcriptomic, and genomic data from 156 molecularly diverse glioblastoma (GBM) tumors and derivative models. Through integrated analysis of the GBM lipidome with molecular datasets, we identify CDKN2A deletion remodels the GBM lipidome, notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments. Consequently, CDKN2A-deleted GBMs display higher lipid peroxidation, selectively priming tumors for ferroptosis. Together, this study presents a molecular and lipidomic resource of clinical and preclinical GBM specimens, which we leverage to detect a therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM.

Keywords: CDKN2A; GPX4; RNA sequencing; ferroptosis; glioblastoma; lipid droplet; lipid peroxidation; shotgun lipidomics; triacylglyceride.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Ferroptosis* / genetics
  • Ferroptosis* / physiology
  • Gene Expression Profiling
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Lipid Metabolism* / genetics
  • Lipid Metabolism* / physiology
  • Neoplasm Recurrence, Local

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16