METB-16. ACQUISITION OF WARBURG PHENOTYPE IN IDH1-MUTATED GLIOMA AS A MECHANISM OF MALIGNANT TRANSFORMATION

Abstract

The Warburg effect is one of the hallmarks of cancer metabolism and its prevalence includes gliomas. The formation of lactate and upregulation of glycolysis has been the basis of many studies that either use 18FDG PET or lactate as a readout of cancer progression. However, IDH1-mutated gliomas have been reported to have low glycolytic rates and minimal lactate production, due to the hypermethylation of the promoter region of LDHA. We postulated that initially, IDH1-mutated gliomas form very little lactate, but as they progress towards glioblastomas lactate production increases. TS603 and BT142 cell lines harboring IDH1 mutation were cultured in DMEM/F12+ N2 supplement, glutamine, FGF and EGF, then either harvested for metabolomics and methylation analyses or (250,000 cells) were injected into 6-week-old SCID mice brains. MRI was used to monitor tumor size; when tumors reached 100 mm3, mice were injected in the tail vain with 96 mM 1-13C pyruvate which was hyperpolarized using Oxford Hypersense hyperpolarizer and chemical shift images were acquired immediately. Metabolite quantification was done using the Agilent LC/MS 6545 QTOF mass spectrometer. DNA methylation analysis was performed using Illumina Human Methylation 450 Bead Chip. Our results demonstrate a unique example of IDH1-mutant glioma that transformed to a highly glycolytic, Warburg-like glioma that was associated with loss of global methylation and increased expression of glycolytic enzymes. Moreover, the glycolytic enzyme expression of the aggressive cell line correlates with the subset of patients that are IDH1 mutated and low-G-CIMP in TCGA database. The results of this study represent an example of malignant transformation that is linked with loss of methylation as a primary step in the mechanism by which IDH1-mutated low grade gliomas transform towards glioblastomas.