Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and treatment

Abstract

The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1–mutated ( IDH1 -mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 ( IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far–unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma

“…A third super-regulon gene, MSRB2 , encodes methionine-R-sulfoxide reductase a multifunctional enzyme that both scavenges reactive oxygen species and is involved in the biosynthesis of cysteine, a key component of GSH, which regulates ferroptosis 57 . All genes in the ETV7 regulon were significantly upregulated in IDH1 mutants ( Figure 5E ), a key finding that was also reproduced in an independent cohort 59 ( Supplementary Figure 5 ). The mechanistic hypotheses were validated by the CRISPR-Cas9 screen 31 , which showed that ETV7 significantly altered proliferation in one glioblastoma stem cell, POU3F2 altered proliferation in three glioblastoma stem cells, and CTCF altered proliferation in seven glioblastoma stem cell lines.…”

Metabolic fingerprinting by nuclear magnetic resonance of hepatocellular carcinoma cells during p53 reactivation‐induced senescence

“…High-resolution 1 H-NMR spectroscopy is widely applied in metabolomics to identify and quantify metabolic alterations in preclinical or clinical studies. 24,[27][28][29][30] High-resolution 1 H-NMR spectroscopy of control and senescent H-Ras cells, a model for p53 reactivation-induced senescence, revealed several altered hydrophilic metabolites (Figure 2, Figure S4, Figure S5). Senescent H-Ras cells presented elevated GPC and reduced PC levels compared with those of control cells, suggesting altered phospholipid metabolism.…”

Acute and chronic inflammation alter immunometabolism in a cutaneous delayed-type hypersensitivity reaction (DTHR) mouse model

“…These glycerophospholipid changes have been associated with pro-and anti-inflammatory activity via plasmalogen hydrolysis, cell membrane property changes, and inflammatory cascade triggering 56 . A switch from choline to ethanolamine metabolism has been previously shown as part of rapid cell growth and repair in environments such as tumour 57,58 . Moreover, a recent study by Fuchs et al 38 showed a similar build-up of O-phosphoethanolamine in M1 macrophages, resulting in reduced mitochondrial respiration and a reduced inflammatory response 38 .…”