Energy Stress in Brain Tumor Initiating Stem Cells

描述(申请人提供)：人脑是新陈代谢最活跃的器官之一，具有高效提取葡萄糖作为能源和碳源的主要货币的能力。特别是，神经元的与众不同之处在于它们有能力 通过高亲和力葡萄糖转运蛋白的表达，优先从营养受限的环境中吸收葡萄糖。最常见的原发脑瘤，胶质母细胞瘤，是人类最致命的癌症之一。与正常大脑一样，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。这些脑瘤始动细胞 显示治疗耐药性，促进肿瘤血管生成，并侵袭正常组织，为建立其调控模型和开发靶向策略提供了理论基础。我们最近证明，脑肿瘤起始细胞通过神经元葡萄糖转运蛋白GLUT3的共同选择，在肿瘤大脑中发现的营养水平降低的情况下表现出显著的生存能力。相比之下，非干细胞样瘤细胞在营养限制的情况下死亡，存活细胞中的细胞可塑性向干细胞样状态转变。总体而言，这些研究发现了一种与肿瘤细胞层次相关的新的分子机制，该机制可能提供一个脆弱的节点，因为靶向GLUT3表达减少了脑瘤启动细胞自我更新和肿瘤生长。像所有癌症一样，胶质母细胞瘤表现出沃堡效应，这是一种优先利用有氧糖酵解提供能量的方式。这种有氧糖酵解使细胞不再需要氧气，并提供稳定的合成代谢物质，但葡萄糖效率很低，需要稳定的葡萄糖供应，这表明它是一个潜在的治疗靶点。基于这一背景，我们假设优先摄取葡萄糖可以保护脑瘤起始细胞免受细胞外能量压力的影响，并提供一种能力，使这些细胞占据不同的生态位，具有不同的代谢限制。抗血管生成的贝伐单抗在肿瘤对治疗的初步反应中表现出了希望，但未能延长生存期。研究表明，血管生成抑制物抵抗与血管功能受损和代谢改变有关，这些改变可能会丰富肿瘤起始细胞。为了研究细胞代谢和肿瘤分级之间的潜在联系，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逆性中的作用。在第二个目标中，我们将通过在动物研究中使用来自人类患者的区域活检和区域特异性GLUT3修饰来询问不同肿瘤微环境中葡萄糖摄取的作用。最后，我们将研究以贝伐单抗或生酮饮食疗法为靶点的GLUT3的潜在合成致死性。我们将使用一系列来自人类胶质母细胞瘤和癫痫组织的模型，为这种致命的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 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.