Metabolism Informs Intertumoral & Intratumoral Heterogeneity

描述(申请人提供)：大脑是代谢最活跃的器官之一，葡萄糖是最重要的，但不是唯一的能量和碳来源。与所有癌症一样，胶质母细胞瘤是最常见和最恶性的原发脑肿瘤，需要持续不断的能量和分子资源来产生新的细胞，优先使用有氧糖酵解，即公认的Warburg效应。有氧糖酵解减少了对氧气的需求，而能量的低效释放允许残存的碳被分流到生产细胞成分。胶质母细胞瘤是一种高度致命的癌症类型，到目前为止，几乎所有的靶向治疗药物都显示出最小的或没有持续的临床益处。未能治愈的原因很多，但我们和其他人将自我更新、高度致瘤性的胶质瘤干细胞(GSCs)与治疗耐药、侵袭正常组织和增加血管生成联系在一起。靶向GSCs可以抑制肿瘤生长，并使肿瘤对传统疗法敏感。在这项应用中，两个具有互补研究重点的领先GSC实验室联手检查GSC与新陈代谢之间的关系。异柠檬酸脱氢酶1(IDH1)突变直接联系低级别胶质瘤和继发性胶质母细胞瘤的转化和代谢，但这些突变在胶质母细胞瘤中相对罕见，这表明可能存在替代代谢改变。我们的两个 研究小组询问了GSC在细胞层次内的葡萄糖代谢(肿瘤内异质性)和肿瘤之间的葡萄糖代谢(肿瘤间异质性)。在初步研究中，我们发现，模拟肿瘤条件的营养限制通过在分化细胞中优先存活和获得干细胞样特征来丰富GSC。GSC通过表达一种特殊的、高亲和力的神经元葡萄糖转运蛋白(GLUT3)来优先摄取葡萄糖来响应低糖。GLUT3富含GSCs，靶向GLUT3表达可抑制干细胞自我更新和肿瘤生长。GSC不是一成不变的，而是在治疗过程中演变的。神经胶质母细胞瘤和间充质胶质母细胞瘤的GSC表现出不同的基因表达谱和辐射敏感性，间充质GSCs的糖酵解活性增加。辐射诱导原神经向间充质的转变，伴随着糖酵解代谢和乙醛脱氢酶活性的激活。由于选定的代谢结节可用于治疗靶点，我们假设Warburg效应通过细胞层级和克隆进化机制对胶质瘤的异质性起因果作用。在这项应用中，第一个目标将确定肿瘤微环境重新编程葡萄糖摄取，以指导胶质母细胞瘤的细胞分级。作为一项独立但互为补充的研究，第二个目标将确定糖酵解重编程在胶质瘤干细胞获得治疗耐药的进化中的作用。这些研究的最终目标是通过结合细胞等级理论和克隆进化理论来建立一个新的概念，以更好地阐明肿瘤异质性的机制，并针对导致对当前治疗方案产生抵抗力的不同分子建立靶向治疗。拟议的研究完成后，将挑战当前的研究和临床实践障碍，并将通过开发一种新的策略来针对新发现的胶质母细胞瘤的代谢变化来创建一条坚实的翻译途径。

DESCRIPTION (provided by applicant): The brain is one of the most metabolically active organs with glucose representing the most important, but not the only, source of energy and carbon. Like all cancers, glioblastoma, the most prevalent and malignant primary brain tumor, requires a continuous source of energy and molecular resources for new cell production with a preferential use of aerobic glycolysis, recognized as the Warburg effect. Aerobic glycolysis diminishes the need for oxygen, while inefficient liberation of energy permits residual carbons to be shunted to produce cellular components. Glioblastoma is a highly lethal cancer type with almost all targeted therapeutics tested to date showing minimal to no sustained clinical benefit. The failure to achieve cure has many causes, but we and others have linked self-renewing, highly tumorigenic glioma stem cells (GSCs) to therapeutic resistance, invasion into normal tissues, and increased angiogenesis. Targeting GSCs can inhibit tumor growth and sensitize tumors to conventional therapies. In this application, two leading GSC laboratories with complementary research foci have joined forces to examine the relationship between GSCs and metabolism. Isocitrate dehydrogenase 1 (IDH1) mutations directly link transformation and metabolism in low grade gliomas and secondary glioblastoma, but these mutations are relatively rare in glioblastoma, suggesting that alternative metabolic alterations are likely present. Our two groups have interrogated GSC glucose metabolism within the cellular hierarchy (intratumoral heterogeneity) and between tumors (intertumoral heterogeneity). In preliminary studies, we found that nutrient restriction mimicking tumor conditions enriches for GSCs through preferential GSC survival and acquisition of stem- like features in differentiated cells. GSCs respond to low glucose by preferential uptake of glucose through the expression of a specialized, high affinity neuronal glucose transporter (Glut3). Glut3 enriches for GSCs and targeting Glut3 expression attenuates stem cell self-renewal and tumor growth. GSCs are not static, but rather evolve during treatment. GSCs from proneural and mesenchymal glioblastomas display differential gene expression profiles and radiation sensitivity with increased glycolytic activity in mesenchymal GSCs. Radiation induces a proneural-to-mesenchymal transition associated with activation of glycolytic metabolism and aldehyde dehydrogenase activity. As selected metabolic nodes are amenable to therapeutic targeting, we hypothesize that the Warburg effect causally contributes to glioma heterogeneity through cellular hierarchical and clonal evolution mechanisms. In this application, the first aim will determine the tumor microenvironment reprograms glucose uptake to instruct glioblastoma cellular hierarchies. As an independent yet complementary study, the second aim will determine the role of glycolytic reprogramming in the evolution of glioma stem cells to acquire therapeutic resistance. The ultimate goals of these studies are to establish a new concept by incorporating both the cellular hierarchical theory and the clonal evolution theory to better clarify the mechanism of tumor heterogeneity and to establish targeted therapies for distinct molecules that are responsible for a gain of resistance t current therapies. The proposed studies, when completed, will challenge the current research and clinical practice hurdles and will create a firm path to translation by developing a novel strategy to target the newly identified metabolic alterations in glioblastomas.