P02.18.B INTEGRATIVE OMICS ANALYSIS OF IDH1 MUTANT GLIOMA PATIENTS REVEALS ALTERATIONS IN BUTYRATE METABOLISM
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Le résumé fourni par la source
Abstract BACKGROUND Mutations in isocitrate dehydrogenase (IDH) 1 or 2 define glioma classification and determine the biology of these tumors. Although IDH is an essential enzyme in the cellular metabolism, powerful genome-wide analyses focus mostly at the genetic and epigenetic levels, while differences between distinct glioma entities at the proteomics, metabolomics, and functional levels are still poorly understood. Here, we provide an integrative multi-omics analysis of glioma patients to reveal metabolomic vulnerabilities of gliomas stratified by IDH mutation. MATERIAL AND METHODS We performed a multi-omics analysis of two cohorts of glioma patients (n=28) stratified based on IDH mutation status. Molecular assessment included LC-MS analysis, EPIC DNA methylation arrays, RNA-seq/HTA array-based transcriptomics and label-free quantitative proteomics. In 13 patients 13C-glucose was injected prior to surgery and tumor and adjacent brain tissue was collected. Gut microbial profiling using 16S ribosomal RNA (rRNA) sequencing was performed in a separate cohort of 128 glioma patients and 24 healthy individuals. Additional validation was performed in isogenic glioma stem-like cultures with CRISPR knock-in of IDH mutation. RESULTS We show that several molecular layers collectively contribute to biological differences between IDH mutant and wild-type gliomas, with strongest differences observed at the DNA methylation level. IDH mutant gliomas present specific molecular features linked to tumor metabolism. We confirm previous findings on 2-HG, cysteine and de novo glutathione synthesis pathways, which are specifically altered in IDH mutant gliomas. We further identify butyrate metabolism as a novel pathway highly active in IDH mutant gliomas. Butyrate is a bacterial metabolite with multiple systemic effects that is normally synthesized in the gut. This is supported by our gut microbiota metagenomics analysis of glioma patients. Yet the detection of enzymes associated with butyrate metabolism in tumor tissue and cell lines suggests a differential/enhanced metabolic rewiring of the butyrate signaling in IDH mutant gliomas CONCLUSION Our data shows the importance of multiple molecular layers in shaping specific features of IDH mutant gliomas. We unravel an activated butyrate metabolism in IDH mutant gliomas that may underly a novel gut-brain axis in glioma patients.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- P02.18.B INTEGRATIVE OMICS ANALYSIS OF IDH1 MUTANT GLIOMA PATIENTS REVEALS ALTERATIONS IN BUTYRATE METABOLISM
- Date Crossref
- 01/09/2023
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Luxembourg Institute of Health Department of Cancer Research pays non établi dans la noticeOrganisation à but non lucratif
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Cancer Research UK Scotland Institute pays non établi dans la noticeStructure de recherche
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University of Glasgow Cancer Research UK Beatson Institute pays non établi dans la noticeUniversité ou école supérieure
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Laboratoire National de Santé National Center of Genetics pays non établi dans la noticeStructure de recherche
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The University of Texas Health Science Center at Houston Vivian L. Smith Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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University of Luxembourg Luxembourg Centre for Systems Biomedicine (LCSB) pays non établi dans la noticeUniversité ou école supérieure
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Luxembourg Centre for Systems Biomedicine pays non établi dans la noticeUniversité ou école supérieure
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University of Bergen Department of Biomedicine pays non établi dans la noticeUniversité ou école supérieure
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Haukeland University Hospital pays non établi dans la noticeÉtablissement de santé
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NORLUX Neuro-Oncology Laboratory pays non établi dans la noticeStructure de recherche
Department of Cancer Research — Luxembourg Institute of Health, Cancer Research UK Scotland Institute et Cancer Research UK Beatson Institute — University of Glasgow, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.