Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Kristell Oizel 1 Cynthia Chauvin 2, 3, 4 Lisa Oliver 2, 5, 3 Catherine Gratas 3, 5 Fanny Geraldo 3 Ulrich Jarry 2, 4 Emmanuel Scotet 2, 4 Marion Rabe 3 Marie-Clotilde Alves-Guerra 6 Raluca Teusan 7 Fabien Gautier 8, 9 Delphine Loussouarn 9 Vincent Compan 10 Jean-Claude Martinou 11 François Vallette 3, 8, 2, 5, * Claire Pecqueur 3, 2, 5, *
* Corresponding author
1 CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
2 LabEX IGO Immunothérapie Grand Ouest
3 CRCINA - Département ONCO - Equipe 9 - Apoptosis and tumor progression -ATP
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
4 CRCINA - Département INCIT - Equipe 1 - Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
5 Equipe Labellisée Ligue contre le Cancer
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291
8 ICO Nantes - Institut de cancérologie de l'Ouest - Nantes
9 CRCINA - Département ONCO - Equipe 8 - Stress Adaptation and Tumor Escape in breast cancer - SATE
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
10 IGF - Institut de Génomique Fonctionnelle
11 Department of Cell Biology [Geneva, Switzerland]
Abstract : Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for person-alized metabolic targeting of GBM. Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phe-notyping assays, and mitochondrial respirometry. Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN High and GLN Low , mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly pro-liferative GLN High cultures are CD133 neg and display a mesenchymal signature in contrast to CD133 pos GLN Low GBM cells. Conclusions: Our results show that metabolic pheno-typing identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for thera-nostic metabolic targeting. Clin Cancer Res; 1–13. Ó2017 AACR.
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CNRS | UNIV-ANGERS | PAPIN | ICO | GAUDUCHEAU | UNIV-NANTES | FNCLCC | BS | UNIV-MONTPELLIER | UNIV-PARIS5 | CRCINA | USPC | THORAX-UMR | 2IC

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Kristell Oizel, Cynthia Chauvin, Lisa Oliver, Catherine Gratas, Fanny Geraldo, et al.. Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity. Clinical Cancer Research, American Association for Cancer Research, 2017, Epub ahead of print. ⟨10.1158/1078-0432.CCR-16-3102⟩. ⟨inserm-01595798⟩

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