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

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见和最严重的脑癌类型，由一小群自我更新的高度致瘤性细胞（称为胶质母细胞瘤干细胞（GSC））分层组织，对于肿瘤的发生、持续生长和对治疗的抵抗很重要。GSC驻留在血管周围和缺氧的小生境中，这些小生境支持它们的存活和维持它们的干细胞样状态。像所有的癌症一样，GBM显示出瓦尔堡效应，即优先利用有氧糖酵解提供能量。对有氧糖酵解的依赖降低了细胞的氧需求，但葡萄糖的效率很低，需要稳定的葡萄糖供应。在局部葡萄糖缺乏的情况下，居住在营养贫乏的缺氧小生境中的GSC如何供应其增加的葡萄糖需求还知之甚少。我们最近已经表明，GSC优先摄取葡萄糖相比，非GSC或正常细胞通过表达的专门的，高亲和力的葡萄糖转运蛋白亚型，3型（GLUT 3）。GLUT3在包括胚胎干（ES）细胞在内的极少数其他细胞类型中表达，并且在低葡萄糖中培养的非干GBM细胞可以去分化，获得干细胞特征，并表达与存活相关的ES细胞因子NANOG。本研究的目的是检验GSC中的ES细胞样表观遗传重编程通过表达葡萄糖转运蛋白GLUT 3允许抵抗细胞外代谢应激的假设，例如在肿瘤的缺氧小生境中发现的。

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.