Isocitrate dehydrogenase 1–mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress

Abstract

Diffuse gliomas often carry point mutations in isocitrate dehydrogenase (IDH1mut), resulting in metabolic stress. Although IDHmut gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain‐specific tumor–stroma interactions that can compensate for IDH‐1 deficits. To elucidate the metabolic adjustments in clinical IDHmut gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next‐generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH‐1R132H mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1mut‐ and IDHwt‐glioma xenografts. Gene set enrichment analyses of clinical IDH1mut gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDHwt gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDHmut glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDHmut gliomas.—Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W., Span, P. N., Molenaar, R. J., Botman, D., Verrijp, K., Heerschap, A., ter Laan, M., Kusters, B., van Ewijk, A., Huynen, M. A., van Noorden, C. J. F., Leenders, W. P. J. Isocitrate dehydrogenase 1–mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress. FASEB J. 33, 557–571 (2019). http://www.fasebj.org

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

“…The most dominant changes between IDH1 mut and IDH1 wt gliomas were observed in enzymes and transporter proteins related to aerobic glycolysis and glutaminolyses. These observations confirm the previous findings at the RNA level [10][11][12] and strengthen the theory that both glutamate and lactate are imported and converted into α-ketoglutarate in IDH1 mut gliomas, to decrease metabolic stress caused by the mutation. [10][11][12] The increased import of lactate in IDH1 mut glioma cells results in a lower intracellular pH of tumor cells.…”

“…10 More recently, a relationship between the IDH1 mut and lactate and glutamate dependency in glioma has been proposed. 11,12 Based on targeted RNA sequencing of a large series of metabolic enzymes, it was shown that enzymes transporting glutamate and lactate into the cell and enzymes converting lactate and glutamate into α-ketoglutarate are upregulated in IDH1 mut gliomas. 11 It was suggested that IDH1 mut gliomas depend on lactate and glutamate as metabolic substrates to alleviate metabolic stress as a result of defective isocitrate processing.…”

“…11,12 Based on targeted RNA sequencing of a large series of metabolic enzymes, it was shown that enzymes transporting glutamate and lactate into the cell and enzymes converting lactate and glutamate into α-ketoglutarate are upregulated in IDH1 mut gliomas. 11 It was suggested that IDH1 mut gliomas depend on lactate and glutamate as metabolic substrates to alleviate metabolic stress as a result of defective isocitrate processing. 11 In this study we validate previously obtained RNA expression data at the protein level and in addition studied the pentose phosphate pathway, TCA cycle, aerobic glycolysis, glutaminolysis, fatty acid metabolism, GABA shunt, and amino acid catabolism.…”

“…11 It was suggested that IDH1 mut gliomas depend on lactate and glutamate as metabolic substrates to alleviate metabolic stress as a result of defective isocitrate processing. 11 In this study we validate previously obtained RNA expression data at the protein level and in addition studied the pentose phosphate pathway, TCA cycle, aerobic glycolysis, glutaminolysis, fatty acid metabolism, GABA shunt, and amino acid catabolism. To perform the proteomics mapping of the pathways, FFPE tissue samples of astrocytomas, oligodendrogliomas and GBMs were investigated.…”

Metabolic reprogramming in the pathogenesis of glioma: Update

“…Of interest, IDH mutations are recently reported to be involved in multi‐layered metabolic activities in gliomas. Diffuse glioma cells with IDH mutations are dependent on glutamate and lactate, possibly supplied by neurons and astrocytes, and the dependency on these metabolites could open the way to novel approaches for treating IDH ‐mutant gliomas . The altered metabolic landscape in IDH ‐mutant gliomas also affects phospholipid, energy, and oxidative stress pathways .…”