Lactate metabolism in H3K27M mutant diffuse midline gliomas

Abstract

Metabolic reprogramming driven by oncogenes is a cancer hallmark that enables tumor cells to consume nutrients in vast quantities to support their unchecked proliferation. Our laboratory has shown that the H3K27M mutation in Diffuse Midline Glioma (DMG), driven by the Warburg effect, enhances glycolysis and promotes lactate production. Historically/conventionally, lactate was thought to be a metabolic waste product. However, recent studies have challenged this notion by demonstrating numerous biological roles for lactate in various disease settings. This includes the acidification of the tumor microenvironment, immune suppression, and a fuel for mitochondrial energy production. These discoveries have prompted our efforts to investigate the role of lactate metabolism in DMG. Despite its recognized roles in other cancer types, lactate’s contribution to DMG biology is not well characterized. This study explores its energetic utilization by DMG cells. Using liquid chromatography/mass spectrometry (LC/MS) in isogenic mouse neuronal stem cells, we find that H3K27M, compared to H3 WT cells, have elevated intracellular lactate levels. Furthermore, patient-derived DMG cells utilize lactate as an energy source in nutrient-depleted conditions. Notably, genetic and pharmacologic inhibition of lactate dehydrogenase (LDHA & LDHB) hinders cell growth. These findings suggest that lactate metabolism plays a critical role in the physiology of DMG cells and warrant further investigation into its potential role in driving DMG cancer progression.