GSE171163
Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress
Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy number amplified in the majority of glioblastomas. ASNS copy number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSCs), we showed significant metabolic alterations occur in gliomas when perturbing the expression of asparagine synthetase, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis which led to radiation resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. Overall design: RNA sequencing on glioma stem cells (ASNS-high and -low) underwent irradiation and cultured for 0, 3 and 14 days with control cells without irradiation.