Metabolic Reprogramming Associated with Aggressiveness Occurs in the G-CIMP-High Molecular Subtypes of IDH1mut Lower Grade Gliomas

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Neuro Oncol


BACKGROUND: Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. IDH-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses towards secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood.

METHODS: We employed model systems for IDH1 mutant gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic we analyzed TCGA data.

RESULTS: We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially LDHA, and have increased mRNA and metabolite levels compared to the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the G-CIMP-high molecular subtype in patients and is associated with the worst outcome.

CONCLUSION: We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness.

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ePub ahead of print