Abstract
Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.
Highlights
Isocitrate dehydrogenase 1 (IDH1) mutations are genetic alterations that are considered driver mutations and occur in 70–90% of lower-grade gliomas (LGG) [1]; faithful models that recapitulate this disease are sparse
Tumor cells reshape their metabolism in order to sustain their rapid growth [5] and this remodeling can be further modified in those cases where mutations occur in pivotal metabolic enzymes, such as isocitrate dehydrogenase 1 (IDH1)
Using nuclear magnetic resonance (NMR) and mass spectrometry-based 13 C-tracing in addition to hyperpolarized magnetic resonance spectral imaging (MRSI), we provide a comprehensive metabolic characterization of this mouse model in comparison with normal tissue, which can serve as a reference metabolic landscape for
Summary
Isocitrate dehydrogenase 1 (IDH1) mutations are genetic alterations that are considered driver mutations and occur in 70–90% of lower-grade gliomas (LGG) [1]; faithful models that recapitulate this disease are sparse. The cancer-associated mutation of IDH has gained a neomorphic activity by catalyzing the conversion of αKG into 2HG while oxidizing NADPH This reaction produces a 50- to 100-fold increase in 2HG levels in cells harboring the mutation [6,7]. This mutation is considered to be a major feature in reshaping the metabolic landscape of tumors such as gliomas [8,9] or fibrosacromas [10], along with a defective activity of the WT reaction, which reversibly interconverts isocitrate and αKG [11]. The findings revealed can be employed for selective targeting of dysregulated metabolic pathways
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