Metabolic symbiosis in glioblastoma rely on lactate dehydrogenase expression and activity. Metabolic adaptations in LDHA/B KO GBM cells

Lactate is a central metabolite in brain physiology, but was also characterized as improving tumor aggressiveness. Glioblastoma (GBM) is the most common and most malignant primary brain tumor in adults. GBMs are recognized by angiogenic and invasive growth, in addition to altered metabolism. GBM stem-like cells are resistant to chemo- and radiotherapy, using either glycolytic or oxidative metabolism. Here we show symbiotic role of lactate by replenishing Krebs cycle in absence of glucose. In a clinically relevant human GBM xenograft model, we demonstrate that lactate dehydrogenases (LDH) A and B, interconverting pyruvate to lactate, drive proliferation, invasion through a symbiotic phenomenon. Consequently, survival was increased in the double LDHA/B KO group while resistance mechanisms relying higher oxidative phosphorylation (OxPhos) were observed. Use of cerebral irradiation on double LDHA/B KO group massively improved survival. Finally, combinatory treatment of antiangiogenic and repurposed antiepileptic drug, targeting LDHA and LDHB activities, also induced improvement in survival.All in all, our data bring a novel view on metabolic symbiosis between glioblastoma stem-like cells and we propose innovative treatment to counteract this phenomenon.