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dc.contributor.authorFack, Freden_US
dc.contributor.authorTardito, Saverioen_US
dc.contributor.authorHochart, Guillaumeen_US
dc.contributor.authorOudin, Anaïsen_US
dc.contributor.authorZheng, Liangen_US
dc.contributor.authorFritah, Sabrinaen_US
dc.contributor.authorGolebiewska, Annaen_US
dc.contributor.authorNazarov, Petren_US
dc.contributor.authorBernard, Amandineen_US
dc.contributor.authorHau, Ann-Christinen_US
dc.contributor.authorKeunen, Olivieren_US
dc.contributor.authorLeenders, William P.J.en_US
dc.contributor.authorLund-Johansen, Mortenen_US
dc.contributor.authorStauber, Jonathanen_US
dc.contributor.authorGottlieb, Eyalen_US
dc.contributor.authorBjerkvig, Rolfen_US
dc.contributor.authorNiclou, Simone Pierretteen_US
dc.PublishedFack F, Tardito S, Hochart, Oudin A, Zheng L, Fritah S, Golebiewska A, Nazarov P, Bernard A, Hau, Keunen O, Leenders WP, Lund-Johansen M, Stauber, Gottlieb E, Bjerkvig R, Niclou S. Altered metabolic landscape in IDH‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways. EMBO Molecular Medicine. 2017;9(12):1681-1695eng
dc.description.abstractHeterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.en_US
dc.publisherEMBO Presseng
dc.rightsAttribution CC BYeng
dc.subjectIsocitrate Dehydrogenaseeng
dc.subjectMass spectrometryeng
dc.titleAltered metabolic landscape in IDH‐mutant gliomas affects phospholipid, energy, and oxidative stress pathwaysen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright the Author. All rights reserved
dc.source.journalEMBO Molecular Medicine

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