Metabolomics of GBM

Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma (GBM) cells and tissues, with an aim towards identifying potential targetable biomarkers for developing more effective and novel therapies. Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established GBM cells, GBM tissues, and normal human astrocytes. Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRMs) in GBM cells compared to normal human astrocytes (NHAs). Unlike NHAs, GBM cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP) deficient GBM cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in GBM cells. Insilico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in GBM. We validated this result by demonstrating that the exogenous addition of DRMs to GBM cells in vitro, results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of GBM. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for GBM.

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