TY - JOUR
T1 - Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress
AU - Lenting, Krissie
AU - Khurshed, Mohammed
AU - Peeters, Tom H.
AU - van den Heuvel, Corina N. A. M.
AU - van Lith, Sanne A. M.
AU - de Bitter, Tessa
AU - Hendriks, Wiljan
AU - Span, Paul N.
AU - Molenaar, Remco J.
AU - Botman, Dennis
AU - Verrijp, Kiek
AU - Heerschap, Arend
AU - Laan, Mark Ter
AU - Kusters, Benno
AU - van Ewijk, Anne
AU - Huynen, Martijn A.
AU - van Noorden, Cornelis J. F.
AU - Leenders, William P. J.
PY - 2019
Y1 - 2019
N2 - 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 quantitativeRNA next-generation sequencingto 66 clinical gliomas and relevant orthotopicglioma xenografts, with andwithoutthe endogenous IDH-1R132Hmutation.Datasetswere analyzedinRusingManhattanplotsto calculate distancebetween expressionprofiles,Ward'smethodtoperformunsupervised agglomerative clustering, andtheMann 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 fromin situenzymaticmapping studies and preclinicalin vivomagnetic 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.
AB - 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 quantitativeRNA next-generation sequencingto 66 clinical gliomas and relevant orthotopicglioma xenografts, with andwithoutthe endogenous IDH-1R132Hmutation.Datasetswere analyzedinRusingManhattanplotsto calculate distancebetween expressionprofiles,Ward'smethodtoperformunsupervised agglomerative clustering, andtheMann 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 fromin situenzymaticmapping studies and preclinicalin vivomagnetic 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85059245275&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30001166
U2 - https://doi.org/10.1096/fj.201800907RR
DO - https://doi.org/10.1096/fj.201800907RR
M3 - Article
C2 - 30001166
SN - 0892-6638
VL - 33
SP - 557
EP - 571
JO - FASEB Journal
JF - FASEB Journal
IS - 1
ER -