TY - JOUR
T1 - Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways
AU - Fack, Fred
AU - Tardito, Saverio
AU - Hochart, Guillaume
AU - Oudin, Anais
AU - Zheng, Liang
AU - Fritah, Sabrina
AU - Golebiewska, Anna
AU - Nazarov, Petr V.
AU - Bernard, Amandine
AU - Hau, Ann Christin
AU - Keunen, Olivier
AU - Leenders, William
AU - Lund-Johansen, Morten
AU - Stauber, Jonathan
AU - Gottlieb, Eyal
AU - Bjerkvig, Rolf
AU - Niclou, Simone P.
N1 - Funding Information:
The authors thank Virginie Baus for excellent technical assistance with the animal work and acknowledge the financial contribution of the Luxembourg Institute of Health (Luxembourg) and the Stiftelsen Kristian Gerhard Jebsen (Norway). The authors would like to dedicate this publication to our dear colleague Chantal Courtois, who passed away during the resubmission of this work.
Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2017/12
Y1 - 2017/12
N2 - Heterozygous 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.
AB - Heterozygous 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.
KW - CBS
KW - glioma
KW - isocitrate dehydrogenase
KW - mass spectrometry imaging
KW - phospholipids
UR - http://www.scopus.com/inward/record.url?scp=85035775583&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/29054837
U2 - 10.15252/emmm.201707729
DO - 10.15252/emmm.201707729
M3 - Article
C2 - 29054837
AN - SCOPUS:85035775583
SN - 1757-4676
VL - 9
SP - 1681
EP - 1695
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
ER -