Altered metabolic landscape in IDH ‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

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.

A metabolomic data fusion approach to support gliomas grading

“…Reduced serine biosynthesis may lead to increased reliance on the CBS/CTH pathway as a critical response to increased oxidative stress . In particular, high CBS expression has been shown to confer better prognosis in IDH ‐mutated 1p/19q codeleted gliomas in line with a previous study showing that decreased expression of CBS promotes glioma tumorigenesis in tumor xenografts . Correlation between higher CBS expression and survival in IDH ‐mutated 1p/19q codeleted gliomas has been confirmed also from the POLA public dataset .…”

“…Correlation between higher CBS expression and survival in IDH ‐mutated 1p/19q codeleted gliomas has been confirmed also from the POLA public dataset . Fack et al have reported decreased Cyst in IDH mutant tumour xenografts compared with wild type, yet in the few samples reported in this last study, Cyst levels were roughly inversely correlated with codeletion status …”

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

“…It is, however, striking that the glycolysis route that fuels the TCA cycle is not increased (the glucose importer SLC2A3 RNA expression is even decreased). The obstructed catabolism of glucose in IDH1 mut gliomas was reported before . By metabolic flux experiments in an IDH1 R132H patient‐derived xenograft (PDX) it was shown that glucose is scarcely used as the carbon source for either α‐ketoglutarate or 2‐hydroxy‐glutarate, indicative of the use of alternative carbon sources for the production of these metabolites to fuel the TCA‐cycle .…”

In vivo 1H MRS detection of cystathionine in human brain tumors

“…Additionally, our observations suggested that cystathionine increase is associated with enhanced cystathionine beta‐synthase activity likely due to a compensatory mechanism induced by oxidative stress, and that this process may be exacerbated in the presence of 1p/19q codeletion due to reduced activity of cystathionine gamma‐lyase (located on chromosome 1p) . Notably, high cystathionine beta‐synthase expression was suggested to confer better prognosis in IDH ‐mutated gliomas with 1p/19q codeletion . Further investigations are needed to evaluate the possible role of cystathionine as a marker of antioxidative activity in brain tumors and, eventually, its prognostic value.…”