Integrative cross-platform analyses identify enhanced heterotrophy as a metabolic hallmark in glioblastoma.
Amino Acids
/ metabolism
Astrocytoma
/ genetics
Brain Neoplasms
/ genetics
Carcinogenesis
Cellular Reprogramming
DNA Methylation
DNA Modification Methylases
/ genetics
DNA Repair Enzymes
/ genetics
Gene Expression Profiling
Glioblastoma
/ genetics
Humans
Isocitrate Dehydrogenase
/ genetics
Lipid Metabolism
Metabolomics
Mutation
Neoplasm Grading
Peptides
/ metabolism
Tumor Suppressor Proteins
/ genetics
genomics
glioblastoma
integrative analyses
intratumoral heterogeneity
metabolomics
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
19 02 2019
19 02 2019
Historique:
pubmed:
27
11
2018
medline:
6
5
2020
entrez:
27
11
2018
Statut:
ppublish
Résumé
Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing to the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis. Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n = 28] and glioblastoma [n = 80]) were performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models. Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide, and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing to a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models. Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes to a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy.
Sections du résumé
BACKGROUND
Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing to the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis.
METHODS
Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n = 28] and glioblastoma [n = 80]) were performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models.
RESULTS
Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide, and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing to a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models.
CONCLUSION
Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes to a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy.
Identifiants
pubmed: 30476237
pii: 5172259
doi: 10.1093/neuonc/noy185
pmc: PMC6380409
doi:
Substances chimiques
Amino Acids
0
Peptides
0
Tumor Suppressor Proteins
0
Isocitrate Dehydrogenase
EC 1.1.1.41
DNA Modification Methylases
EC 2.1.1.-
MGMT protein, human
EC 2.1.1.63
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
337-347Informations de copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
J Biol Chem. 1996 Apr 26;271(17):9982-6
pubmed: 8626637
Nat Rev Cancer. 2016 Nov;16(11):732-749
pubmed: 27658529
Science. 2018 May 11;360(6389):660-663
pubmed: 29748285
Cancer Res. 2014 Feb 1;74(3):787-96
pubmed: 24351290
Nat Med. 2013 Jul;19(7):901-908
pubmed: 23793099
Clin Cancer Res. 2016 Nov 1;22(21):5337-5348
pubmed: 27281560
Neuro Oncol. 2017 Nov 29;19(12):1599-1606
pubmed: 28541485
Nat Rev Cancer. 2016 Oct;16(10):650-62
pubmed: 27634448
Br J Cancer. 2006 Oct 9;95(7):869-78
pubmed: 16969344
N Engl J Med. 2009 Feb 19;360(8):765-73
pubmed: 19228619
Neurosurgery. 2008 Feb;62(2):493-503; discussion 503-4
pubmed: 18382329
J Neurooncol. 2013 Jan;111(1):11-8
pubmed: 23086431
Clin Cancer Res. 2016 Oct 1;22(19):4797-4806
pubmed: 27143690
Cancer Cell. 2010 Jan 19;17(1):98-110
pubmed: 20129251
Cell Metab. 2012 Jun 6;15(6):827-37
pubmed: 22682223
J Neurosci. 2005 Aug 3;25(31):7101-10
pubmed: 16079392
Cancer Cell. 2012 Mar 20;21(3):297-308
pubmed: 22439925
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
pubmed: 18032601
N Engl J Med. 2005 Mar 10;352(10):997-1003
pubmed: 15758010
Clin Cancer Res. 2018 Aug 1;24(15):3632-3643
pubmed: 29691296
Cell Metab. 2013 Aug 6;18(2):153-61
pubmed: 23791484
Science. 2008 Sep 26;321(5897):1807-12
pubmed: 18772396
Nature. 2009 Dec 10;462(7274):739-44
pubmed: 19935646
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14
pubmed: 23412337
Nature. 2010 Jun 17;465(7300):966
pubmed: 20559394
Biochim Biophys Acta. 2012 Apr;1821(4):694-705
pubmed: 22285325
Cancer Discov. 2014 Nov;4(11):1290-8
pubmed: 25182153
Brain Tumor Pathol. 2005;22(2):89-91
pubmed: 18095110
Mol Cancer Res. 2016 Dec;14(12):1229-1242
pubmed: 27658422
Cancer Discov. 2012 Oct;2(10):881-98
pubmed: 23009760
Nat Rev Cancer. 2013 Apr;13(4):227-32
pubmed: 23446547
Cell Metab. 2012 Jul 3;16(1):9-17
pubmed: 22768835
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8644-9
pubmed: 23650391
Cancer Res. 2012 Nov 15;72(22):5878-88
pubmed: 23026133
Nature. 2013 May 30;497(7451):633-7
pubmed: 23665962
Nat Rev Cancer. 2016 Oct;16(10):619-34
pubmed: 27492215
Cancer Cell. 2006 Mar;9(3):157-73
pubmed: 16530701
Science. 2016 Sep 9;353(6304):1161-5
pubmed: 27609895
Glia. 2018 Feb;66(2):327-347
pubmed: 29068088
Nature. 2012 Feb 15;483(7390):474-8
pubmed: 22343901
J Clin Invest. 2015 Feb;125(2):687-98
pubmed: 25607840
Cancer Res. 2015 May 1;75(9):1782-8
pubmed: 25855379