Energy Stress in Brain Tumor Initiating Stem Cells

脑肿瘤起始干细胞中的能量应激

基本信息

批准号：
8785788
负责人：
JEREMY N RICH
金额：
$ 34.67万
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：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785788
关键词：
5&apos -AMP-activated protein kinase Acids Aerobic Affect Affinity Angiogenesis Inhibitors Animals Area Avastin Biopsy Blood Blood - brain barrier anatomy Blood Glucose Blood Vessels Brain Brain Diseases Brain Glioblastoma Brain Neoplasms Brain Stem Carbon Cell Death Cell Lineage Cells Clinical Cues DNA Data Dependence Diet Modification Diet therapy Energy Supply Environment Epilepsy FDA approved Failure Foundations Glioblastoma Glioma Glucose Glucose Transporter Human Hypoxia Invaded Ketone Bodies Link Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolic stress Metabolism Modeling Modification Molecular Nature Necrosis Neurons Neurosciences Normal tissue morphology Nutrient Nutritional Organ Oxygen Patients Perfusion Pharmaceutical Preparations Phenotype Population Prevalence Primary Brain Neoplasms Process Protein Isoforms Radiation Radiation therapy Regulation Reporting Resistance Role SLC2A1 gene Series Solid Neoplasm Source Stem cells Stress Therapeutic Tissues Tumor Angiogenesis Variant Vascular blood supply Warburg Effect aerobic glycolysis aptamer base bevacizumab cell killing chemotherapy conventional therapy deprivation embryonic stem cell extracellular glucose uptake improved ketogenic diet neoplastic neoplastic cell novel palliation preimplantation prevent public health relevance regional difference response self-renewal small hairpin RNA sperm cell stem therapeutic target tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The human brain represents one of the most metabolically active organs with a highly efficient ability to extract glucose as the primary currency for energy and carbon source. In particular, neurons are distinguished in their ability to preferentially absorb glucose from a nutrient-restricted environment through the expression of high affinity glucose transporters. The most prevalent primary brain tumor, glioblastoma, ranks among the most lethal of human cancers. Like the normal brain, glioblastomas contain cellular hierarchies with self-renewing, multi-lineage cells at the apex. These brain tumor initiating cells display therapeutic resistance, promote tumor angiogenesis, and invade into normal tissues providing rationale to model their regulation and develop targeting strategies. We recently demonstrated that brain tumor initiating cells display a marked ability to survive the reduced nutrient levels found in the neoplastic brain through the cooption of the neuronal glucose transporter, GLUT3. In contrast, non-stem cell-like tumor cells underwent cell death with nutrient restriction with a cellular plasticity towards a stem cell-like state in surviving cells. Collectivly, these studies identify a novel molecular mechanism associated with the tumor cellular hierarchy that could provide a node of fragility as targeting GLUT3 expression reduced brain tumor initiating cell self-renewal and tumor growth. Like all cancers, glioblastomas display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. This aerobic glycolyss frees the cells from oxygen requirements and provides a steady supply of anabolic material yet is highly glucose inefficient and requires a steady supply of glucose, suggesting a potential therapeutic target. Based on this background, we hypothesize that preferential glucose uptake shields brain tumor initiating cells from extracellular energy stress and provides an ability to these cells to occupy a diverse set of niches with different metabolic limitations. The anti-angiogenic bevacizumab has shown promise in the initial response of tumors to therapy but has failed to extend survival. Studies have suggested that angiogenic inhibitor resistance is associated with impaired vascular function and metabolic shifts that may enrich for tumor initiating cells. To investigate these potential links between cellular metabolism and the tumor hierarchy, we will dissect the interplay between brain tumor initiating cells and the tumor microenvironment. In the first aim, we will determine the role of the stem cell metabolic responses in stress resistance. In the second aim, we will interrogate the role of glucose uptake in different tumor microenvironments enriched in tumor initiating cells through the use of regional biopsies from human patients and regionally specific Glut3 modification in animal studies. Finally, we will investigate the potential synthetic lethality of targeting GLUT3 with bevacizumab or ketogenic diet therapy. We will employ a series of models derived from human glioblastomas and epilepsy tissues to lay the foundation for advanced modeling of this lethal brain disease.

描述（由申请人提供）：人脑代表着最具代谢活性的器官之一，具有高效的能力，可以提取葡萄糖作为能量和碳源的主要货币。特别是，神经元在其能力方面具有区分优先通过高亲和葡萄糖转运蛋白的表达从营养限制的环境中吸收葡萄糖。最普遍的原发性脑肿瘤，胶质母细胞瘤是最致命的人类癌症之一。像正常的大脑一样，胶质母细胞瘤包含细胞层次结构，并在顶点处具有自我更新，多型细胞。这些脑肿瘤引发细胞表现出治疗性耐药性，促进肿瘤血管生成，并入侵正常组织，提供基本原理来建模其调节并制定靶向策略。我们最近证明，通过神经元葡萄糖转运蛋白Glut3的粪便，脑肿瘤引发的细胞具有明显的能力，可在肿瘤大脑中生存降低的营养水平。相反，非茎细胞样肿瘤细胞在养分限制中经历了细胞死亡，并在存活细胞中对干细胞状状态具有细胞可塑性。集体研究，这些研究确定了一种与肿瘤细胞层次结构相关的新型分子机制，该机制可以提供脆弱的节点，因为靶向GLUT3表达会减少脑肿瘤，从而启动细胞自我更新和肿瘤生长。像所有癌症一样，胶质母细胞瘤显示出沃堡效应，这是对能量供应的有氧糖糖溶解的优先利用。这种有氧甘油可以使细胞免于氧气需求，并提供合成代谢材料的稳定供应，但高度葡萄糖效率高，需要稳定的葡萄糖供应，这表明潜在的治疗靶标。基于这种背景，我们假设优先的葡萄糖摄取屏蔽了脑肿瘤从细胞外能量应力引发细胞，并为这些细胞提供了具有不同代谢限制的各种壁ni的能力。抗血管生成贝伐单抗在肿瘤对治疗的初始反应中表现出了希望，但未能延长生存率。研究表明，血管生成抑制剂的耐药性与可能富含肿瘤启动细胞的血管功能和代谢转移有关。为了研究细胞代谢与肿瘤层次结构之间的这些潜在联系，我们将剖析脑肿瘤启动细胞与肿瘤微环境之间的相互作用。在第一个目标中，我们将确定干细胞代谢反应在应激抗性中的作用。在第二个目标中，我们将通过使用人类患者的区域活检和动物研究中的区域特定的GLUT3修饰来审问葡萄糖吸收在不同肿瘤微环境中的作用。最后，我们将研究用贝伐单抗或生酮饮食疗法靶向GLUT3的潜在合成致死性。我们将采用一系列源自人胶质母细胞瘤和癫痫组织的模型，为这种致命的脑疾病的高级建模奠定了基础。