Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis
Joris Guyon, Ignacio Fernández‐Moncada, Claire Larrieu, Cyrielle Bouchez, Antonio C. Pagano Zottola, Johanna Galvis, Tiffanie Chouleur, Audrey Burban, Kevin Joseph, Vidhya M. Ravi, Heidi Espedal, Gro Vatne Røsland, Boutaina Daher, Aurélien Barré, 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 Miletić, Dieter Henrik Heiland, Giovanni Marsicano, Macha Nikolski, Rolf Bjerkvig, Andréas Bikfalvi, Thomas Daubon
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.