Stem Cell Phenotype, GLUT3 expression, and Metabolic Stress Resistance in Gliobla

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Glioblastoma (GBM), the most common and severe type of brain cancer, are hierarchically organized with a small subpopulation of self-renewing highly tumorigenic cells, termed glioblastoma stem cells (GSCs), important for tumor initiation, continued growth, and resistance to therapies. GSCs reside in perivascular and hypoxic niches that support their survival and the maintenance of their stem-like state. Like all cancers, GBMs display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. Reliance upon aerobic glycolysis reduces cellular oxygen requirements yet is highly glucose inefficient and requires a steady glucose supply. How GSCs residing in the nutrient-poor hypoxic niche can supply their increased glucose demands amidst local glucose scarcity is poorly known. We have recently shown that GSCs preferentially uptake glucose compared to non-GSCs or normal cells through expression of the specialized, high-affinity glucose transporter isoform, type 3 (GLUT3). GLUT3 is expressed in very few other cell types, including embryonic stem (ES) cells, and non-stem GBM cells cultured in low glucose can de-differentiate, gain stem cell characteristics, and express the ES cell factor NANOG, correlating with survival. The goal of this research is to test the hypothesis that ES cell-like epigenetic reprogramming in GSCs allows resistance to extracellular metabolic stress, such as found in the hypoxic niche of tumors, through expression of the glucose transporter GLUT3.