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

描述(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，由一小部分自我更新的高度致癌细胞组成，称为胶质母细胞瘤干细胞(GSCs)，对肿瘤的启动、持续生长和对治疗的抵抗至关重要。GSCs存在于血管周围和低氧环境中，支持其存活和维持其干细胞样状态。像所有的癌症一样，GBM表现出沃堡效应，这是一种优先利用有氧糖酵解提供能量的方式。对有氧糖酵解的依赖降低了细胞的需氧量，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，生长在营养贫乏的低氧生态位中的GSCs如何满足其增加的葡萄糖需求尚不清楚。我们最近发现，与非GSCs或正常细胞相比，GSCs通过表达特殊的高亲和力葡萄糖转运体3型(GLUT3)优先摄取葡萄糖。GLUT3在极少数其他类型的细胞中表达，包括胚胎干细胞，在低糖培养的非干细胞GBM细胞可以去分化，获得干细胞特征，并表达ES细胞因子NANOG，与生存相关。这项研究的目的是检验这一假设，即在GSCs中类似ES细胞的表观遗传重新编程允许通过表达葡萄糖转运蛋白GLUT3来抵抗细胞外代谢应激，例如在肿瘤的缺氧区。

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.