Microenvironmental-derived Regulation of HIF-Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme. Microenvironmental-derived Regulation of HIF-Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme

The evolving and highly heterogeneous nature of malignant brain tumors underlies their limited response to therapy and poor prognosis. In addition to genetic alterations, highly dynamic processes such as transcriptional and metabolic reprograming play an important role in the development of tumor heterogeneity. The present study reports an adaptive mechanism in which the metabolic environment of malignant glioma drives transcriptional reprogramming. Multi-regional analysis of a glioblastoma patient biopsy revealed a metabolic landscape marked by varying stages of hypoxia and creatine enrichment. Creatine treatment and metabolism was further shown to promote a synergistic effect through up-regulation of the glycine-cleavage system and chemical regulation of Prolyl-Hydroxylase Domain (PHD). Consequently, creatine maintained a reduction of reactive oxygen species and change of the a-ketoglutarate/succinate ratio leading to an inhibition of the HIF-signaling in primary tumor cell lines. These effects shifted the transcriptional pattern toward a proneural subtype and reduced the rate of cell migration and invasion in vitro. Overall design: For metabolic treatment, different metabolites were supplemented into the medium. Creatine-enriched environment was simulated by 15 mMol creatine supplementation. Cells were cultured under normoxic (21% O2) or hypoxic (3% O2) conditions.