Abstract
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.
Highlights
Gliomas are a heterogeneous group of glial-derived brain tumors, the majority of which have a poor prognosis
We applied in situ metabolic profiling and liquid chromatography–mass spectrometry (LC-mass spectrometry (MS)) on brain sections of glioma patientderived xenografts (PDX) and human glioma samples with and without the IDH1 mutation for large-scale unbiased metabolic profiling of these tumors
It should be noted that based on our current understanding, isocitrate dehydrogenase (IDH)-mutant and IDH wild-type gliomas represent biologically different entities and it is currently not clear which differences can be directly attributed to the IDH status
Summary
Gliomas are a heterogeneous group of glial-derived brain tumors, the majority of which have a poor prognosis. IDH mutations are present in the vast majority of lower grade gliomas and define a subtype with a favorable prognosis (Hartmann et al, 2009; Yan et al, 2009). They have recently been recognized as the major determinant in the molecular classification of diffuse gliomas (Cancer Genome Atlas Research et al, 2015; Ceccarelli et al, 2016). Of the two isoforms associated with tumorigenesis, cytosolic IDH1 is the most commonly mutated, while the mitochondrial IDH2 isoform represents < 5% of mutant cases (Hartmann et al, 2009). While IDH1 and IDH2 are NADP+-dependent enzymes, the mitochondrial NAD-dependent IDH3 isoform has not been associated with mutations
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