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，被称为胶质母细胞瘤干细胞（GSCs）的一小群自我更新的高度致瘤性细胞分层组织，对肿瘤的起始、持续生长和对治疗的抵抗很重要。GSCs存在于血管周围和低氧壁龛中，这支持它们的生存和维持它们的茎样状态。像所有癌症一样，GBMs表现出Warburg效应，即优先利用有氧糖酵解来提供能量。依靠有氧糖酵解减少细胞对氧的需求，但葡萄糖效率低，需要稳定的葡萄糖供应。在缺乏营养的缺氧生态位中，GSCs如何在局部葡萄糖稀缺的情况下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通过表达特化的、高亲和力的葡萄糖转运蛋白异构体3型（GLUT3），优先摄取葡萄糖。GLUT3在极少数其他细胞类型中表达，包括胚胎干细胞（ES）细胞和低糖培养的非干细胞GBM细胞可以去分化，获得干细胞特征，并表达与存活相关的ES细胞因子NANOG。本研究的目的是验证一种假设，即GSCs中的胚胎干细胞样表观遗传重编程可以通过表达葡萄糖转运体GLUT3来抵抗细胞外代谢应激，例如在肿瘤的缺氧生态位中发现的应激。

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.