Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.

Autor: Guyon J; University Bordeaux, INSERM U1312, BRIC, Pessac, France., Fernandez-Moncada I; University Bordeaux, INSERM, U1215 Neurocentre Magendie, Bordeaux, France., Larrieu CM; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Bouchez CL; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Pagano Zottola AC; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Galvis J; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France.; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Chouleur T; University Bordeaux, INSERM U1312, BRIC, Pessac, France., Burban A; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Joseph K; Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg, Freiburg, Germany.; Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Translational NeuroOncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany.; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany., Ravi VM; Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg, Freiburg, Germany.; Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Translational NeuroOncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany.; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany.; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany., Espedal H; NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway., Røsland GV; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Daher B; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Barre A; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Dartigues B; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Karkar S; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Rudewicz J; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Romero-Garmendia I; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Klink B; Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.; German Cancer Consortium (DKTK), Dresden, Germany.; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany., Grützmann K; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany., Derieppe MA; Animal Facility, University Bordeaux, Pessac, France., Molinié T; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France., Obad N; NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway., Léon C; University Bordeaux, INSERM U1312, BRIC, Pessac, France., Seano G; Institut Curie, INSERM U1021, CNRS UMR3347, Tumor Microenvironment Lab, University Paris-Saclay, Orsay, France., Miletic H; NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway.; Department of Pathology, Haukeland University Hospital, Bergen, Norway., Heiland DH; Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg, Freiburg, Germany.; Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Translational NeuroOncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany., Marsicano G; University Bordeaux, INSERM, U1215 Neurocentre Magendie, Bordeaux, France., Nikolski M; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France.; Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France., Bjerkvig R; NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway., Bikfalvi A; University Bordeaux, INSERM U1312, BRIC, Pessac, France., Daubon T; University Bordeaux, INSERM U1312, BRIC, Pessac, France.; University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2022 Dec 07; Vol. 14 (12), pp. e15343. Date of Electronic Publication: 2022 Oct 24.
DOI: 10.15252/emmm.202115343
Abstrakt: 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.
(© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
Externí odkaz: