Format

Send to

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

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

Author information

1
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
2
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands.
4
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Department of Cell Biology, Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands.
6
Radiotherapy and Oncoimmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
7
Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands; and.
8
Center for Molecular and Biomolecular Informatics, Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands.

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

PMID:
30001166
DOI:
10.1096/fj.201800907RR

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center