Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities
Luciano Garofano
(1, 2)
,
Simona Migliozzi
(1)
,
Young Taek Oh
(1)
,
Fulvio d'Angelo
(1)
,
Ryan Najac
(1)
,
Aram Ko
(1)
,
Brulinda Frangaj
(1)
,
Francesca Pia Caruso
(2)
,
Kai Yu
(3)
,
Jinzhou Yuan
(4, 1)
,
Wenting Zhao
(4, 1)
,
Anna Luisa Di Stefano
(5, 6, 7)
,
Franck Bielle
(5, 8)
,
Tao Jiang
(9)
,
Peter Sims
(4, 1)
,
Mario Suvà
(10, 11)
,
Fuchou Tang
(3)
,
Xiao-Dong Su
(3)
,
Michele Ceccarelli
(2)
,
Marc Sanson
(5, 6)
,
Anna Lasorella
(1)
,
Antonio Iavarone
(1)
,
Fulvio D’angelo
(1)
1
CUMC -
Columbia University Medical Center
2 University of Naples Federico II = Università degli studi di Napoli Federico II
3 Peking University [Beijing]
4 Columbia University [New York]
5 ICM - Institut du Cerveau = Paris Brain Institute
6 CHU Pitié-Salpêtrière [AP-HP]
7 Hôpital Foch [Suresnes]
8 Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]
9 CUMS - Capital University of Medical Sciences [Beijing]
10 BROAD INSTITUTE - Broad Institute of MIT and Harvard
11 Massachusetts General Hospital [Boston, MA, USA]
2 University of Naples Federico II = Università degli studi di Napoli Federico II
3 Peking University [Beijing]
4 Columbia University [New York]
5 ICM - Institut du Cerveau = Paris Brain Institute
6 CHU Pitié-Salpêtrière [AP-HP]
7 Hôpital Foch [Suresnes]
8 Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]
9 CUMS - Capital University of Medical Sciences [Beijing]
10 BROAD INSTITUTE - Broad Institute of MIT and Harvard
11 Massachusetts General Hospital [Boston, MA, USA]
Luciano Garofano
- Fonction : Auteur
- PersonId : 1208219
- ORCID : 0000-0001-8582-0865
Francesca Pia Caruso
- Fonction : Auteur
- PersonId : 1385369
- ORCID : 0000-0002-2206-1459
Tao Jiang
- Fonction : Auteur
- PersonId : 1385370
- ORCID : 0000-0002-7008-6351
Fuchou Tang
- Fonction : Auteur
- PersonId : 1293965
- ORCID : 0000-0002-8625-7717
Michele Ceccarelli
- Fonction : Auteur
- PersonId : 1208218
- ORCID : 0000-0002-4702-6617
Anna Lasorella
- Fonction : Auteur
- PersonId : 1208224
- ORCID : 0000-0002-1839-5421
Antonio Iavarone
- Fonction : Auteur
- PersonId : 1208225
- ORCID : 0000-0002-0683-4634
Fulvio D’angelo
- Fonction : Auteur
- PersonId : 1208226
- ORCID : 0000-0002-4940-4693
Résumé
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.