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

FASEB J. 2019 Jan;33(1):557-571. doi: 10.1096/fj.201800907RR. Epub 2018 Jul 12.

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.

Keywords: anaplerosis; diffuse infiltration; glycolysis; metabolism; neurotransmitters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminobutyrate Transaminase / genetics
  • 4-Aminobutyrate Transaminase / metabolism
  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology*
  • Glutamate Dehydrogenase / genetics
  • Glutamate Dehydrogenase / metabolism
  • Glutamic Acid / metabolism*
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Lactic Acid / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation*
  • Neoplasm Invasiveness
  • Stress, Physiological*
  • Succinate-Semialdehyde Dehydrogenase / genetics
  • Succinate-Semialdehyde Dehydrogenase / metabolism
  • Transcriptome
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Lactic Acid
  • Glutamic Acid
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • ALDH5A1 protein, human
  • Succinate-Semialdehyde Dehydrogenase
  • Glutamate Dehydrogenase
  • GLUD1 protein, human
  • 4-Aminobutyrate Transaminase
  • GLS1 protein, human
  • Glutaminase