Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in preclinical models of H3K27M-mutant gliomas
Menée à l'aide de modèles de gliome infiltrant du tronc cérébral avec mutation H3K27M, cette étude met en évidence un mécanisme par lequel la mutation H3K27M favorise la production de lactate à partir de glucose ainsi que la biosynthèse de nucléotides puis démontre l'intérêt de ce processus pour suivre l'évolution de la maladie et la réponse thérapeutique à l'aide de l'imagerie métabolique au deutérium
Hyperactivation of glucose metabolism to lactate is a metabolic hallmark of cancer. However, the functional role of lactate in pediatric diffuse midline glioma (DMG) cells is unclear. Here, using stable isotope tracing and loss-of-function studies in clinically relevant patient-derived DMG models, we show that the oncogenic histone H3K27M mutation epigenetically up-regulates the rate-limiting glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U-13C]-glucose in DMGs. Mechanistically, lactate posttranslationally activates the nucleoside diphosphate kinase NME1 through lactylation and facilitates the synthesis of nucleoside triphosphates that are essential for DNA replication and tumor proliferation. This mechanistic link between glycolysis and nucleotide biosynthesis provides the opportunity for deuterium metabolic imaging of tumor growth and response to therapy. Spatially mapping 2H-lactate production from [6,6-2H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard of care and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations in tumor tissues in preclinical DMG models in vivo at clinical field strength (3 T). Overall, we have identified an H3K27M-lactate-NME1 axis that drives DMG proliferation and facilitates noninvasive in vivo metabolic imaging of DMGs. H3K27M-driven lactylation facilitates nucleotide biosynthesis, an effect that can be exploited for metabolic imaging of disease progression in DMGs. Diffuse midline gliomas (DMGs) are malignant pediatric brain tumors with frequent mutations in histone H3. Here, Batsios et al. define a role for histone H3 in glucose to lactate metabolism that could be exploited for disease monitoring through imaging. They show that H3K27M mutations specifically up-regulate glucose metabolism to lactate, which drives tumor proliferation. They next investigate the use of glucose metabolism as a metabolic imaging modality to evaluate response to targeted therapy to better guide treatment in preclinical models. This represents promising noninvasive in vivo metabolic imaging that could help guide treatment for patients with DMG. —Dorothy Hallberg
Science Translational Medicine , résumé, 2026