Targeting TCA cycle in Brain Tumor Initiating Cells

 描述（由申请人提供）：人脑是代谢最活跃的器官之一，具有高效提取葡萄糖作为能量和碳源的主要货币的能力。特别是，神经元在它们的能力， 通过表达高亲和力葡萄糖转运蛋白，优先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人类最致命的癌症之一。像正常的大脑一样，胶质母细胞瘤包含细胞层次结构，顶端有自我更新的多谱系细胞。这些脑肿瘤起始细胞 显示治疗抗性，促进肿瘤血管生成，并侵入正常组织，为模拟其调节和开发靶向策略提供了理论基础。我们最近证明，脑肿瘤起始细胞显示出显著的能力，通过神经元葡萄糖转运蛋白GLUT 3的协同作用，在肿瘤性脑中发现的营养水平降低的情况下存活。相比之下，非干细胞样肿瘤细胞在营养限制下经历细胞死亡，在存活细胞中具有朝向干细胞样状态的细胞可塑性。总的来说，这些研究确定了一种与肿瘤细胞层次相关的新分子机制，该机制可以提供一个脆弱的节点，因为靶向GLUT 3表达减少了脑肿瘤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瓦尔堡效应，即优先利用有氧糖酵解提供能量。这种有氧糖酵解释放细胞的氧气需求，并提供稳定的合成代谢物质的供应，但葡萄糖是高度低效的，需要稳定的葡萄糖供应，这表明一个潜在的治疗目标。基于这一背景，我们假设优先使用葡萄糖衍生的碳骨架进行大分子生物合成允许脑肿瘤起始细胞在细胞外能量应激下存活，并为这些细胞提供了占据具有不同代谢限制的不同生态位的能力。抗血管生成的贝伐单抗在肿瘤对治疗的最初反应中显示出希望，但未能延长生存期。研究表明，血管生成抑制剂耐药性与血管功能受损和可能富集肿瘤起始细胞的代谢变化有关。为了研究细胞代谢和肿瘤等级之间的这些潜在联系，我们将剖析脑肿瘤起始细胞和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抗应激中的作用。在第二个目标中，我们将通过使用来自人类患者的区域活检和动物研究中的区域特异性SIRT 3修饰来询问线粒体蛋白的翻译后修饰在肿瘤起始细胞中富集的不同肿瘤微环境中的作用。最后，我们将研究用化疗和/或放疗靶向SIRT 3的潜在合成致死性。我们将采用一系列来自人类胶质母细胞瘤和癫痫组织的模型，为这种致命性脑部疾病的高级建模奠定基础。

 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 use of glucose-derived carbon backbones for macromolecular biosynthesis allows brain tumor initiating cells to survive under 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 post-translational modification of mitochondrial proteins in different tumor microenvironments enriched in tumor initiating cells through the use of regional biopsies from human patients and regionally specific SIRT3 modification in animal studies. Finally, we will investigate the potential synthetic lethality of targeting SIRT3 with chemotherapy and/or radiation. 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.