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, Aurelien
AU - Dartigues, Benjamin
AU - Karkar, Slim
AU - Rudewicz, Justine
AU - Romero-Garmendia, Irati
AU - Klink, Barbara
AU - Grützmann, Konrad
AU - Derieppe, Marie-Alix
AU - Molinie, Thibaut
AU - Obad, Nina
AU - Leon, Celine
AU - Seano, Giorgio
AU - Miletic, Hrvoje
AU - Heiland, Dieter Henrik
AU - Marsicano, Giovanni
AU - Bjerkvig, Rolf
AU - Bikfalvi, Andreas
AU - Daubon, Thomas
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 - glioblastoma (GBM)
KW - metabolic symbiosis
KW - tumor invasion
UR - http://www.scopus.com/inward/record.url?scp=85140370735&partnerID=8YFLogxK
U2 - 10.15252/emmm.202115343
DO - 10.15252/emmm.202115343
M3 - Article
C2 - 36278433
SN - 1757-4684
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e15343
ER -