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 GrützmannMarie 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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere15343
JournalEMBO Molecular Medicine
Volume14
Issue number12
Early online date24 Oct 2022
DOIs
Publication statusPublished - 7 Dec 2022

Keywords

  • antiepileptic drug
  • energy metabolism
  • glioblastoma
  • invasion
  • lactate dehydrogenases

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