CDKN2A Deletion Remodels Lipid Metabolism to Prime Glioblastoma for Ferroptosis

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2023 May 26

PMID 37236196

Authors

Jenna K Minami

Danielle Morrow

Nicholas A Bayley

Elizabeth G Fernandez

Jennifer J Salinas

Christopher Tse

Henan Zhu

Baolong Su

Rhea Plawat

Anthony Jones

Alessandro Sammarco

Linda M Liau

Thomas G Graeber

Kevin J Williams

Timothy F Cloughesy

Scott J Dixon

Steven J Bensinger

David A Nathanson

Affiliations

Soon will be listed here.

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.

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