CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis
Menée à l'aide de sphéroïdes, de xénogreffes et d'échantillons tumoraux issus de patients atteints d'un glioblastome, cette étude met en évidence un mécanisme par lequel la délétion du gène CDKN2A, en modifiant le métabolisme des lipides, sensibilise les cellules cancéreuses à la ferroptose
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.
Cancer Cell , article en libre accès, 2022