Metabolism Informs Intertumoral & Intratumoral Heterogeneity

描述（由申请人提供）：大脑是代谢最活跃的器官之一，葡萄糖是最重要但不是唯一的能量和碳源。与所有癌症一样，胶质母细胞瘤是最普遍和恶性的原发性脑肿瘤，需要持续的能量和分子资源来源用于新细胞的产生，优先使用有氧糖酵解，这被认为是瓦尔堡效应。有氧糖酵解减少了对氧气的需求，而能量的低效率释放允许剩余的碳被分流以产生细胞成分。胶质母细胞瘤是一种高度致命的癌症类型，迄今为止测试的几乎所有靶向疗法都显示出最小或没有持续的临床益处。未能实现治愈有很多原因，但我们和其他人已经将自我更新，高度致瘤性胶质瘤干细胞（GSC）与治疗抗性，侵入正常组织和增加血管生成联系起来。靶向GSC可以抑制肿瘤生长并使肿瘤对常规疗法敏感。在此应用中，两个具有互补研究重点的领先GSC实验室联手研究GSC与代谢之间的关系。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，表明可能存在替代代谢改变。我们两 研究小组已经研究了细胞层次内（肿瘤内异质性）和肿瘤之间（肿瘤间异质性）的GSC葡萄糖代谢。在初步研究中，我们发现模拟肿瘤条件的营养限制通过优先GSC存活和在分化细胞中获得干细胞样特征来富集GSC。GSC通过表达特异性的高亲和力神经元葡萄糖转运蛋白（Glut3）优先摄取葡萄糖来响应低葡萄糖。Glut3富集GSC，靶向Glut3表达减弱干细胞自我更新和肿瘤生长。GSC不是静态的，而是在治疗过程中演变。来自前神经和间充质胶质母细胞瘤的GSC显示差异基因表达谱和辐射敏感性，其中间充质GSC中的糖酵解活性增加。辐射诱导前神经向间充质转化，与糖酵解代谢和醛脱氢酶活性的激活相关。由于选定的代谢节点是服从治疗靶向，我们假设，瓦尔堡效应因果地有助于通过细胞层次和克隆进化机制的胶质瘤异质性。在该应用中，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细胞层级。作为一项独立但互补的研究，第二个目标将确定糖酵解重编程在胶质瘤干细胞进化中的作用，以获得治疗抗性。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产生耐药性的不同分子建立靶向治疗。拟议的研究完成后，将挑战目前的研究和临床实践障碍，并将通过开发一种新的策略来靶向胶质母细胞瘤中新发现的代谢改变，从而创造一条坚定的翻译道路。

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.