CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis

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

doi:10.1016/j.ccell.2023.05.001

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.

Authors

Jenna K Minami¹, Danielle Morrow¹, Nicholas A Bayley¹, Elizabeth G Fernandez¹, Jennifer J Salinas¹, Christopher Tse¹, Henan Zhu¹, Baolong Su², Rhea Plawat¹, Anthony Jones¹, Alessandro Sammarco², Linda M Liau³, Thomas G Graeber⁴, Kevin J Williams⁵, Timothy F Cloughesy⁶, Scott J Dixon⁷, Steven J Bensinger⁸, David A Nathanson⁹

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁴ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ UCLA Lipidomics Core, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁷ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: sjdixon@stanford.edu.
⁸ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Lipidomics Core, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: sbensinger@mednet.ucla.edu.
⁹ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: dnathanson@mednet.ucla.edu.

PMID: 37236196
PMCID: PMC10330677 (available on 2024-06-12)
DOI: 10.1016/j.ccell.2023.05.001

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding