Metabolism Informs Intertumoral & Intratumoral Heterogeneity

代谢为肿瘤间提供信息

基本信息

批准号：
8829932
负责人：
Ichiro Nakano
金额：
$ 40.71万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829932
关键词：
Affinity Attenuated Blood flow Brain Carbon Cell Maintenance Cell Survival Cells Clinical Clonal Evolution Energy-Generating Resources Evolution Failure Genetic Glioblastoma Glioma Glucose Glucose Transporter Glycolysis Goals Growth Health Heterogeneity Hypoxia Hypoxia Inducible Factor Isocitrate Dehydrogenase Laboratories Link Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Mesenchymal Mesenchymal Cell Neoplasm Metabolic Metabolism Modeling Molecular Molecular Profiling Mutation Nature Neurons Normal tissue morphology Nutrient Organ Oxygen Phenotype Primary Brain Neoplasms Production Property Radiation Radiation Tolerance Radiation therapy Reporting Research Residual state Resistance Resources Role Stem cells Stress Testing Tissue-Specific Gene Expression Translations Warburg Effect aerobic glycolysis aldehyde dehydrogenases angiogenesis cancer stem cell cancer type chemotherapy clinical practice conventional therapy glucose metabolism glucose uptake novel strategies pre-clinical self-renewal stem targeted treatment theories therapeutic target therapy resistant transcription factor tumor tumor growth tumor microenvironment tumorigenic

项目摘要

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.

描述（由申请人提供）：大脑是代表葡萄糖最重要但不是唯一的能源和碳来源的最活跃的器官之一。像所有癌症一样，胶质母细胞瘤，最普遍，最恶性的原发性脑肿瘤，需要连续的能量和分子资源来源，用于新细胞产生，并优先使用有氧糖糖溶解，被认为是沃堡效应。有氧糖酵解减少了对氧气的需求，而能量的效率低下允许将残留的碳分解以产生细胞成分。胶质母细胞瘤是一种高度致命的癌症类型，迄今为止，几乎所有靶向的治疗剂都显示出最低限于持续临床益处。无法实现治疗的原因有许多原因，但是我们和其他人已经将自我更新，高度肿瘤性神经胶质瘤干细胞（GSC）与治疗性耐药性，侵入正常组织以及血管生成增加联系在一起。靶向GSC可以抑制肿瘤生长并使肿瘤对常规疗法敏感。在此应用程序中，两个具有互补研究焦点的GSC领先实验室已联手研究GSC与代谢之间的关系。等级神经胶质瘤和继发性胶质母细胞瘤中的异位酸脱氢酶1（IDH1）突变直接连接转化和代谢，但是这些突变在胶质母细胞瘤中相对较少，这表明可能存在替代的代谢改变。我们的两个组询问了细胞层次结构内的GSC葡萄糖代谢（肿瘤内异质性）和肿瘤之间（肿瘤间异质性）。在初步研究中，我们发现，通过优先的GSC存活和分化细胞中的茎类特征的获取，营养限制模仿了肿瘤条件的GSC。 GSC通过优先摄取葡萄糖的葡萄糖来反应低葡萄糖，通过表达高的高亲和力神经元葡萄糖转运蛋白（GLUT3）。 GLUT3富集GSC，靶向GLUT3表达会减弱干细胞的自我更新和肿瘤生长。 GSC不是静态的，而是在治疗过程中进化。来自原质和间充质胶质母细胞瘤的GSC显示出差异基因表达谱和辐射敏感性，并在间充质GSC中增加糖酵解活性。辐射诱导与糖酵解代谢和醛脱氢酶活性的激活相关的负肌向间质转变。由于选定的代谢淋巴结与治疗靶向相吻合，因此我们假设Warburg效应通过细胞分层和克隆进化机制有因果关系有助于神经胶质瘤异质性。在此应用中，第一个目标将决定肿瘤微环境重编程葡萄糖摄取以指导胶质母细胞瘤细胞层次结构。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神经胶质瘤干细胞进化中获得治疗性抗性的作用。这些研究的最终目标是通过纳入细胞等级理论和克隆进化论来建立一个新概念，以更好地阐明肿瘤异质性的机制，并为抗药性t当前疗法获得的不同分子建立有针对性的疗法。拟议的研究完成后，将挑战当前的研究和临床实践障碍，并通过制定一种新型策略来瞄准新近确定的胶质母细胞瘤的代谢改变，从而创造牢固的翻译道路。