TY - JOUR
T1 - Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis
AU - Guyon, Joris
AU - Fernandez-Moncada, Ignacio
AU - Larrieu, Claire M.
AU - Bouchez, Cyrielle L.
AU - Pagano Zottola, Antonio C.
AU - Galvis, Johanna
AU - Chouleur, Tiffanie
AU - Burban, Audrey
AU - Joseph, Kevin
AU - Ravi, Vidhya M.
AU - Espedal, Heidi
AU - Røsland, Gro Vatne
AU - Daher, Boutaina
AU - Barre, Aurélien
AU - Dartigues, Benjamin
AU - Karkar, Slim
AU - Rudewicz, Justine
AU - Romero-Garmendia, Irati
AU - Klink, Barbara
AU - Grützmann, Konrad
AU - Derieppe, Marie Alix
AU - Molinié, Thibaut
AU - Obad, Nina
AU - Léon, Céline
AU - Seano, Giorgio
AU - Miletic, Hrvoje
AU - Heiland, Dieter Henrik
AU - Marsicano, Giovanni
AU - Nikolski, Macha
AU - Bjerkvig, Rolf
AU - Bikfalvi, Andreas
AU - Daubon, Thomas
N1 - Funding Information:
This work was supported by grants from Centre National de la Recherche Scientifique ‐ France (CNRS) and INSERM (recurrent fundings) and the “Ligue Contre le Cancer” (N°228841#1) and the Fondation ARC (N°216415#1), Association pour la Recherche sur les Tumeurs Cérébrales (N°225119#1), PLBIO INCa (N°227441#1), Cancéropôle GSO (N°2020‐EC29), and the SIRIC‐BRIO to TD and AB and by Helse Vest, Haukeland Hospital, The Norwegian Research Council and Stiftelsen Kristian Gerhard Jebsen Research Foundation for RB. CB is a recipient of SIRIC BRIO funding for her postdoctoral position. The authors thank Dr Jubayer A Hossain, Dr Matthias Preussler, and Matteo Gambarreti for preliminary experiments, Pr Marina Kreutz, Pr Kathrin Jenner, Sonja‐Maria Decking and Nathalie Babl, and then Maxime Toujas and Lucie Brisson for their help during the revision process, Arnaud Villacreces and Dr Jean‐Max Pasquet from the « CellOxia, modeling the hypoxic niche » facility for their technical assistance (Univ. Bordeaux, INSERM U1035, F‐33000 Bordeaux, France), the VIB‐CCB Metabolomics Expertise Center for the 13C‐lactate metabolic analyses, with Pr Bart Ghesquiere, and MetaToul facility for 13C‐glucose analysis and their expertise (Lindsay Peyriga, Florian Bellvert, Pr Jean‐Charles Portais et Maud Heuillet), Biocodex for providing stiripentol (Marc Verleye), Dr Florence Cavalli for advising the use of bioinformatics tools, Dr Yapeng Li from Peking University for proving all details on IP LDHA and activity, and Dr Arnaud Mourier for the constructive criticism of the manuscript and performed experiments. We are also grateful for the work done by Marcia Campistron and Marie‐Paule Algeo from Animalerie Mutualisee de Talence. The microscopy was done in the Bordeaux Imaging Center, a service unit of the CNRS‐INSERM and Bordeaux University, a member of the national infrastructure France BioImaging supported by the French National Research Agency (ANR‐10‐INBS‐04).
Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/12/7
Y1 - 2022/12/7
N2 - 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.
AB - 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.
KW - antiepileptic drug
KW - energy metabolism
KW - glioblastoma
KW - invasion
KW - lactate dehydrogenases
UR - http://www.scopus.com/inward/record.url?scp=85140370735&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36278433
U2 - 10.15252/emmm.202115343
DO - 10.15252/emmm.202115343
M3 - Article
C2 - 36278433
SN - 1757-4676
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e15343
ER -