Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities - Sorbonne Université Access content directly
Journal Articles Nature Cancer Year : 2021

Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities

Fuchou Tang
Anna Lasorella
Antonio Iavarone
Fulvio D’angelo

Abstract

The transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism.

Dates and versions

hal-04587157 , version 1 (24-05-2024)

Identifiers

Cite

Luciano Garofano, Simona Migliozzi, Young Taek Oh, Fulvio d'Angelo, Ryan Najac, et al.. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nature Cancer, 2021, 2 (2), pp.141-156. ⟨10.1038/s43018-020-00159-4⟩. ⟨hal-04587157⟩
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