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

Autor: Corina N. A. M. van den Heuvel, Arend Heerschap, Kiek Verrijp, Wiljan Hendriks, Paul N. Span, Martijn A. Huynen, Cornelis J.F. Van Noorden, Mohammed Khurshed, Krissie Lenting, Benno Küsters, Remco J. Molenaar, Tom H Peeters, Anne van Ewijk, William P.J. Leenders, Mark ter Laan, Tessa J. J. de Bitter, Sanne A. M. van Lith, Dennis Botman
Přispěvatelé: Cell Biology and Histology, Graduate School, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, CCA - Cancer biology and immunology, Medical Biology
Rok vydání: 2018
Předmět:
0301 basic medicine
In vivo magnetic resonance spectroscopy
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Biochemistry
Transcriptome
Mice
0302 clinical medicine
Glutamate Dehydrogenase
Tumor Cells
Cultured
Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]
Glycolysis
Mice
Inbred BALB C
Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17]
Brain Neoplasms
Chemistry
Glutamate receptor
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
Glioma
Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Isocitrate Dehydrogenase
Gene Expression Regulation
Neoplastic
Isocitrate dehydrogenase
Succinate-Semialdehyde Dehydrogenase
Biotechnology
Glutamic Acid
Mice
Nude
03 medical and health sciences
Glutaminase
Stress
Physiological
Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15]
Genetics
medicine
Animals
Humans
Neoplasm Invasiveness
Lactic Acid
Molecular Biology
Gene Expression Profiling
medicine.disease
Xenograft Model Antitumor Assays
Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10]
Glutamine
Metabolic pathway
030104 developmental biology
4-Aminobutyrate Transaminase
Mutation
Cancer research
Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
030217 neurology & neurosurgery
Zdroj: FASEB journal, 33(1), 557-571. FASEB
The Faseb Journal, 33, 1, pp. 557-571
The Faseb Journal, 33, 557-571
ISSN: 1530-6860
0892-6638
DOI: 10.1096/fj.201800907rr
Popis: Contains fulltext : 202248.pdf (Publisher’s version ) (Closed access) Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1(mut)), resulting in metabolic stress. Although IDH(mut) 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 IDH(mut) 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-1(R132H) 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 IDH1(mut)- and IDH(wt)-glioma xenografts. Gene set enrichment analyses of clinical IDH1(mut) gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDH(wt) 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 IDH(mut) 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 IDH(mut) 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.
Databáze: OpenAIRE
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