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Pré-Publication, Document De Travail Année : 2021

Specific expression of lactate dehydrogenases in glioblastoma controls intercellular lactate transfer to promote tumor growth and invasion

Joris Guyon
Ignacio Fernandez-Moncada
  • Fonction : Auteur
Claire Larrieu
  • Fonction : Auteur
Cyrielle Bouchez
  • Fonction : Auteur
Tiffanie Chouleur
  • Fonction : Auteur
Heidi Espedal
Gro Røsland
Boutaina Daher
Aurelien Barre
  • Fonction : Auteur
Benjamin Dartigues
  • Fonction : Auteur
Aurelien Coffe
  • Fonction : Auteur
Justine Rudewicz
  • Fonction : Auteur
Irati Romero-Garmendia
  • Fonction : Auteur
Barbara Klink
Konrad Grützmann
  • Fonction : Auteur
Marie-Alix Derieppe
  • Fonction : Auteur
Thibaut Molinié
Nina Obad
  • Fonction : Auteur
Céline Leon
  • Fonction : Auteur
Hrvoje Miletic
  • Fonction : Auteur
Giovanni Marsicano
Macha Nikolski
Rolf Bjerkvig
Andreas Bikfalvi

Résumé

Abstract Lactate is a central metabolite in brain physiology, involved in the astrocyte-neuron lactate shuttle, but also contributes to tumor development. Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. By adapting their glycolytic or oxidative metabolism, GBM stem-like cells are able to resist chemo- and radiotherapy. We show herein that lactate fuels GBM anaplerosis by replenishing the TCA cycle in absence of glucose. Lactate dehydrogenases (LDH) catalyze the interconversion of pyruvate and lactate. Deletion of either LDHA or LDHB did not alter significantly GBM growth and invasion. However, ablation of both LDH isoforms led to a reduction of tumor growth, and, consequently, to an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OxPhos) in the double LDHA/B KO group which sensitized tumors to cranial irradiation, massively improving mouse survival. Survival was also increased when control mice were treated with the antiangiogenic treatment, bevacizumab, and the antiepileptic drug, stiripentol which targets LDH activity. Taken together, this highlights the complex metabolic network in which both LDH A and B are integrated and underscores that combined inhibition of LDHA and B is necessary to impact tumor development. Targeting of these enzymes in combination with anti-angiogenic and repurposed drugs may be of therapeutic benefit, especially when associated with radiotherapy.

Domaines

Cancer

Dates et versions

hal-03442170 , version 1 (23-11-2021)

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Citer

Joris Guyon, Ignacio Fernandez-Moncada, Claire Larrieu, Cyrielle Bouchez, Tiffanie Chouleur, et al.. Specific expression of lactate dehydrogenases in glioblastoma controls intercellular lactate transfer to promote tumor growth and invasion. 2021. ⟨hal-03442170⟩

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