Dynamic Complexity of Brain Tumor Stem Cells

脑肿瘤干细胞的动态复杂性

• 批准号: 8955796
• 负责人: JEREMY N RICH
• 金额: $ 95.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955796
• 关键词: Affinity; Astrocytes; Brain; Brain Neoplasms; Brain Stem; Cells; Clinical Trials; Combined Modality Therapy; Complex; Cues; Cytotoxic Chemotherapy; Degenerative Disorder; Development; Ecosystem; Elements; Enhancers; Excision; Failure; GLUT-3 protein; Genetic; Glioblastoma; Glioma; Glucose Transporter; Heterogeneity; Human; Immune; Link; Longevity; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Metabolic; Metabolic Control; Metabolic stress; Metabolism; Mitochondria; Modality; Modeling; Molecular; Morphology; Neoplasm Metastasis; Neuraxis; Neurons; Normal tissue morphology; Nutrient; Oncogenic; Operative Surgical Procedures; Oral; Organ; Oxygen; Patients; Phenocopy; Power Plants; Quality of life; Radiation; Regulation; Regulatory Pathway; Resistance; Role; Stem cells; Therapeutic; Transcriptional Regulation; Tumor Stem Cells; Tumor Suppressor Proteins; Variant; biological adaptation to stress; brain metabolism; cancer cell; cancer stem cell; conventional therapy; epigenetic regulation; improved; killings; neoplastic; neoplastic cell; nerve stem cell; novel; public health relevance; relating to nervous system; response; self-renewal; stem; stem cell niche; temozolomide; tumor; tumor initiation; tumorigenesis

 DESCRIPTION (provided by applicant): Glioblastomas rank among the most lethal of human cancers despite aggressive multimodal therapy. Most cancers kill their hosts through metastases but glioblastomas are nearly universally deadly in the absence of spread beyond the neuraxis due to spread into normal brain and resistance to conventional therapies. The lifespan and quality-of-life for glioblastoma patients has improved with better surgical resection, refined radiation administration and the addition of the oral methylator, temozolomide, during radiation, but median survival remains less than two years. The explanation for the failure of current therapy to extend patient survival has many causes, but one contributing force may be the presence of complex intratumoral heterogeneity derived from heterogeneous expression of oncogenic drivers as well as cellular hierarchies that phenocopy the normal brain hierarchy, albeit with aberrant control. Glioblastomas, like all cancers, can be considered a complex ecosystem that effectively responds to anti-tumor defenses of the body and additional cytotoxic therapy through the collective action of the neoplastic compartment in concert with infiltrating immune cells, vasculature, and reactive astrocytes that can act both as tumor suppressor and enhancer. Normal tissue specific stem cells pose danger due to their ability to undergo sustained proliferation. In response, stem cells reside in specific niches from which their derive maintenance cues but are also constrained in proliferation and undergo differentiation upon exiting the niche. Cancer stem cells share some cell autonomous regulatory pathways with the stem cells in the organs from which they were derived but also recreate elements of a niche. The stem cell niche is a structural construct but also is associated with regional variation in oxygen, pH, and nutrient availability. Thus, it is almost certain that the metabolic reprogramming that occurs within the context of oncogenesis represents an element of the cancer stem cell niche that requires control of metabolic stress responses. Aberrant metabolic control is required for tumor initiation and maintenance. Genetic derangements hardwire self-renewal into tumors but the cellular hierarchy is maintained through the interplay between core stem cell intrinsic transcriptional regulation, metabolism, and niche cues. We recently demonstrated that brain tumor stem cells coopt a high affinity glucose transporter (GLUT3) expressed in neurons to withstand metabolic stress. As mitochondrial morphology is linked to lineage specification, we investigated another mechanism critical to brain metabolism, mitochondrial dynamics. In preliminary studies, we found that brain tumor stem cells displayed molecular regulation distinct from non-stem tumor cells and neural progenitor cells. As targeting mitochondrial dynamics has been linked to neural protection in degenerative disease, these results suggest that targeting mitochondrial dynamics may represent a selective point of fragility for brain tumor stem cells. In the proposed studies we will investigate the role of mitochondrial dynamics and metabolic control in the maintenance of brain tumor stem cells, regulation of the epigenetic stem cell state, and as a therapeutic modality. Collectively, successful completion of the proposed studies will provide an enhanced model of glioma hierarchy and inform the development of novel clinical trials.

 描述（由申请人提供）：胶质母细胞瘤是最致命的人类癌症之一，尽管有积极的多模式治疗。大多数癌症通过转移杀死宿主，但胶质母细胞瘤由于扩散到正常大脑和对常规治疗的抵抗，在没有扩散到神经轴之外的情况下几乎是普遍致命的。胶质母细胞瘤患者的寿命和生活质量随着更好的手术切除而改善， 改进放射治疗和在放射治疗期间增加口服甲基化剂替莫唑胺，但中位生存期仍不到两年。当前治疗未能延长患者生存期的原因有很多，但一个促成因素可能是存在复杂的肿瘤内异质性，这些异质性来源于致癌驱动因子的异质性表达以及细胞层次结构，这些细胞层次结构表型复制正常的大脑层次结构，尽管具有异常控制。胶质母细胞瘤与所有癌症一样，可以被认为是一个复杂的生态系统，通过肿瘤区室与浸润免疫细胞、血管系统和反应性星形胶质细胞的共同作用，有效地响应身体的抗肿瘤防御和额外的细胞毒性治疗，这些细胞可以作为肿瘤抑制剂和增强剂。正常组织特异性干细胞由于其持续增殖的能力而构成危险。作为响应，干细胞驻留在特定的小生境中，它们从该小生境中获得维持信号，但也在增殖中受到限制，并且在离开小生境时经历分化。癌症干细胞与它们所来源的器官中的干细胞共享一些细胞自主调节途径，但也重建了生态位的元素。干细胞生态位是一种结构构建，但也与氧气，pH值和营养物质可用性的区域变化有关。因此，几乎可以肯定的是，在肿瘤发生的背景下发生的代谢重编程代表了需要控制代谢应激反应的癌症干细胞生态位的一个元素。异常代谢控制是肿瘤发生和维持所必需的。遗传紊乱硬线自我更新成肿瘤，但细胞层次是通过核心干细胞内在转录调控，代谢和生态位线索之间的相互作用来维持的。我们最近证明，脑肿瘤干细胞利用神经元中表达的高亲和力葡萄糖转运蛋白（GLUT 3）来承受代谢应激。由于线粒体形态与谱系特化有关，我们研究了对脑代谢至关重要的另一种机制，即线粒体动力学。在初步研究中，我们发现脑肿瘤干细胞显示出与非干肿瘤细胞和神经祖细胞不同的分子调控。由于靶向线粒体动力学与退行性疾病中的神经保护有关，这些结果表明靶向线粒体动力学可能代表脑肿瘤干细胞的选择性脆弱点。在拟议的研究中，我们将研究线粒体动力学和代谢控制在维持脑肿瘤干细胞中的作用，表观遗传干细胞状态的调节， 作为一种治疗方式。总的来说，成功完成拟议的研究将提供一个增强的胶质瘤层次模型，并为新的临床试验的发展提供信息。