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
EMBO Mol Med. 2022-10-24; :
DOI: 10.15252/emmm.202115343

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Guyon J(1), Fernandez-Moncada I(#)(2), Larrieu CM(#)(3), Bouchez CL(#)(3), Pagano Zottola AC(#)(3), Galvis J(3)(4), Chouleur T(1), Burban A(3), Joseph K(5)(6)(7)(8)(9), Ravi VM(5)(6)(7)(8)(9)(10), Espedal H(11), Røsland GV(3), Daher B(3), Barre A(4), Dartigues B(4), Karkar S(4), Rudewicz J(4), Romero-Garmendia I(3), Klink B(12)(13)(14), Grützmann K(14), Derieppe MA(15), Molinié T(3), Obad N(11), Léon C(1), Seano G(16), Miletic H(11)(17), Heiland DH(5)(6)(7)(8)(18), Marsicano G(2), Nikolski M(3)(4), Bjerkvig R(11), Bikfalvi A(1), Daubon T(1)(3).

Author information:
(1)University Bordeaux, INSERM U1312, BRIC, Pessac, France.
(2)University Bordeaux, INSERM, U1215 Neurocentre Magendie, Bordeaux, France.
(3)University Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France.
(4)Bordeaux Bioinformatic Center CBiB, University of Bordeaux, Bordeaux, France.
(5)Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg, Freiburg, Germany.
(6)Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
(7)Faculty of Medicine, University of Freiburg, Freiburg, Germany.
(8)Translational NeuroOncology Research Group, Medical Center, University of Freiburg, Freiburg, Germany.
(9)Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany.
(10)Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany.
(11)NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway.
(12)Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
(13)German Cancer Consortium (DKTK), Dresden, Germany.
(14)Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany.
(15)Animal Facility, University Bordeaux, Pessac, France.
(16)Institut Curie, INSERM U1021, CNRS UMR3347, Tumor Microenvironment Lab,
University Paris-Saclay, Orsay, France.
(17)Department of Pathology, Haukeland University Hospital, Bergen, Norway.
(18)German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany.
(#)Contributed equally

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.


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