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Updated: Jan 4, 2026
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
Metabolic reprogramming associated with aggressiveness occurs in the G-CIMP-high molecular subtypes of IDH1mut lower
Victor Ruiz-Rodado1, Tathiane M Malta2, Tomohiro Seki3
1Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
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. Isocitrate dehydrogenase (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 toward 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 (IDH1mut) 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 data from The Cancer Genome Atlas.
Results:
We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (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.
Insights
Early detection of aggressive brain tumors is challenging. Monitoring lactate levels may indicate metabolic changes and increased tumor aggressiveness in IDH-mutant gliomas.
Area of Science:
- Neuro-oncology
- Cancer Metabolism
- Epigenetics
Background:
- Early detection of aggressive brain tumors remains a challenge.
- Isocitrate dehydrogenase (IDH)-mutant gliomas transform from indolent to aggressive phenotypes.
- Mechanisms of this transformation, including metabolic shifts, are poorly understood.
Purpose of the Study:
- Investigate the link between metabolism and tumor biology in IDH-mutant gliomas.
- Identify molecular features associated with glioma aggressiveness.
- Determine if metabolic reprogramming occurs in clinical glioma subtypes.
Main Methods:
- Utilized in vivo and in vitro IDH1 mutant glioma models.
- Characterized metabolome, transcriptome, and epigenome.
- Analyzed The Cancer Genome Atlas data for clinical correlation.
Main Results:
- Aggressive glioma models showed reduced DNA methylation in glycolytic enzyme promoters (e.g., LDHA).
- Increased mRNA and metabolite levels of glycolytic enzymes were observed in aggressive models.
- High glycolytic phenotype correlated with the G-CIMP-high subtype and poorer outcomes in patients.
Conclusions:
- Metabolic reprogramming, specifically increased glycolysis, is linked to IDH-mutant glioma aggressiveness.
- Lactate levels can serve as a biomarker for metabolic reprogramming and tumor aggressiveness.
- Early monitoring of lactate may aid in detecting increased tumor aggressiveness.
