EMBO Molecular Medicine (Dec 2022)
Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis
- Joris Guyon,
- Ignacio Fernandez‐Moncada,
- Claire M Larrieu,
- Cyrielle L Bouchez,
- Antonio C Pagano Zottola,
- Johanna Galvis,
- Tiffanie Chouleur,
- Audrey Burban,
- Kevin Joseph,
- Vidhya M Ravi,
- Heidi Espedal,
- Gro Vatne Røsland,
- Boutaina Daher,
- Aurélien Barre,
- Benjamin Dartigues,
- Slim Karkar,
- Justine Rudewicz,
- Irati Romero‐Garmendia,
- Barbara Klink,
- Konrad Grützmann,
- Marie‐Alix Derieppe,
- Thibaut Molinié,
- Nina Obad,
- Céline Léon,
- Giorgio Seano,
- Hrvoje Miletic,
- Dieter Henrik Heiland,
- Giovanni Marsicano,
- Macha Nikolski,
- Rolf Bjerkvig,
- Andreas Bikfalvi,
- Thomas Daubon
Affiliations
- Joris Guyon
- University Bordeaux, INSERM U1312, BRIC Pessac France
- Ignacio Fernandez‐Moncada
- University Bordeaux, INSERM, U1215 Neurocentre Magendie Bordeaux France
- Claire M Larrieu
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Cyrielle L Bouchez
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Antonio C Pagano Zottola
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Johanna Galvis
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Tiffanie Chouleur
- University Bordeaux, INSERM U1312, BRIC Pessac France
- Audrey Burban
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Kevin Joseph
- Microenvironment and Immunology Research Laboratory, Medical Center University of Freiburg Freiburg Germany
- Vidhya M Ravi
- Microenvironment and Immunology Research Laboratory, Medical Center University of Freiburg Freiburg Germany
- Heidi Espedal
- NorLux Neuro‐Oncology, Department of Biomedicine University of Bergen Bergen Norway
- Gro Vatne Røsland
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Boutaina Daher
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Aurélien Barre
- Bordeaux Bioinformatic Center CBiB University of Bordeaux Bordeaux France
- Benjamin Dartigues
- Bordeaux Bioinformatic Center CBiB University of Bordeaux Bordeaux France
- Slim Karkar
- Bordeaux Bioinformatic Center CBiB University of Bordeaux Bordeaux France
- Justine Rudewicz
- Bordeaux Bioinformatic Center CBiB University of Bordeaux Bordeaux France
- Irati Romero‐Garmendia
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Barbara Klink
- Department of Oncology Luxembourg Institute of Health Luxembourg Luxembourg
- Konrad Grützmann
- Core Unit for Molecular Tumor Diagnostics (CMTD) National Center for Tumor Diseases (NCT) Dresden Germany
- Marie‐Alix Derieppe
- Animal Facility University Bordeaux Pessac France
- Thibaut Molinié
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Nina Obad
- NorLux Neuro‐Oncology, Department of Biomedicine University of Bergen Bergen Norway
- Céline Léon
- University Bordeaux, INSERM U1312, BRIC Pessac France
- Giorgio Seano
- Institut Curie, INSERM U1021, CNRS UMR3347, Tumor Microenvironment Lab University Paris‐Saclay Orsay France
- Hrvoje Miletic
- NorLux Neuro‐Oncology, Department of Biomedicine University of Bergen Bergen Norway
- Dieter Henrik Heiland
- Microenvironment and Immunology Research Laboratory, Medical Center University of Freiburg Freiburg Germany
- Giovanni Marsicano
- University Bordeaux, INSERM, U1215 Neurocentre Magendie Bordeaux France
- Macha Nikolski
- University Bordeaux, CNRS, IBGC, UMR 5095 Bordeaux France
- Rolf Bjerkvig
- NorLux Neuro‐Oncology, Department of Biomedicine University of Bergen Bergen Norway
- Andreas Bikfalvi
- University Bordeaux, INSERM U1312, BRIC Pessac France
- Thomas Daubon
- University Bordeaux, INSERM U1312, BRIC Pessac France
- DOI
- https://doi.org/10.15252/emmm.202115343
- Journal volume & issue
-
Vol. 14,
no. 12
pp. n/a – n/a
Abstract
Abstract Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.
Keywords