Dynamic Complexity of Brain Tumor Stem Cells

脑肿瘤干细胞的动态复杂性

• 批准号: 9325306
• 负责人: JEREMY N RICH
• 金额: $ 86.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325306
• 关键词: Affinity; Astrocytes; Brain; Brain Stem; Brain Stem Neoplasms; Cells; Clinical Trials; Combined Modality Therapy; Complex; Cues; Cytotoxic Chemotherapy; Degenerative Disorder; Development; Ecosystem; Elements; Enhancers; Excision; Failure; Genetic; Glioblastoma; Glioma; Glucose Transporter; 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; neoplastic; neoplastic cell; nerve stem cell; novel; novel therapeutics; public health relevance; relating to nervous system; response; self-renewal; stem cell differentiation; stem cell niche; stem-like cell; temozolomide; tumor; tumor heterogeneity; tumor initiation; tumorigenesis; Affinity; Astrocytes; Brain; Brain Stem; Brain Stem Neoplasms; Cells; Clinical Trials; Combined Modality Therapy; Complex; Cues; Cytotoxic Chemotherapy; Degenerative Disorder; Development; Ecosystem; Elements; Enhancers; Excision; Failure; Genetic; Glioblastoma; Glioma; Glucose Transporter; 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; neoplastic; neoplastic cell; nerve stem cell; novel; novel therapeutics; public health relevance; relating to nervous system; response; self-renewal; stem cell differentiation; stem cell niche; stem-like cell; temozolomide; tumor; tumor heterogeneity; 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（由适用提供）：胶质母细胞瘤是人类癌症目的地最致命的攻击性多模式疗法之一。大多数癌症通过转移杀死了宿主，但是由于散布到正常的大脑和对常规疗法的抗性，胶质母细胞瘤几乎是普遍致命的。胶质母细胞瘤患者的寿命和生活质量通过更好的外科手术切除有所改善， 在辐射过程中，精制辐射给药和添加了口服甲基替莫唑胺，但中位生存期仍然不到两年。目前疗法延长患者存活的解释是许多原因，但是一种促成力可能是存在于致癌驱动因素的异质表达而得出的复杂的肿瘤内异质性，并且是细胞层次结构，而细胞层次结构是表观对正常脑部层次的表达，即具有异常控制。与所有癌症一样，胶质母细胞瘤可以被认为是一个复杂的生态系统，可以通过与浸润的免疫细胞，脉管和反应性星形胶质细胞兼而有之的肿瘤隔室的集体作用来有效地应对身体的抗肿瘤防御和其他细胞毒性疗法。正常组织特异性干细胞由于其经历持续增殖的能力而构成危险。作为响应，干细胞驻留在其得出维持线索的特定壁ni，但在退出小众时也受到限制并受到分化的限制。癌症干细胞与它们得出的器官中的干细胞共享某些细胞自主调节途径，但也重现了生态位的元素。干细胞生态位是一种结构构建体，但也与氧气，pH和养分可用性的区域变化有关。这几乎可以肯定的是，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裂市场的元素。肿瘤倡议和维护需要异常的代谢控制。遗传进化硬化自我更新为肿瘤，但通过核心干细胞内在的转录调控，代谢和利基线索之间的相互作用来维持细胞层次结构。我们最近证明，脑肿瘤干细胞在神经元中表达以承受代谢应激的高亲和葡萄糖转运蛋白（GLUT3）。由于线粒体形态与谱系规范有关，因此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茎肿瘤细胞和神经元祖细胞不同的分子调节。由于靶向线粒体动力学与退化性疾病中的神经保护有关，因此这些结果表明，靶向线粒体动力学可能代表了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的作用，调节表观遗传干细胞态的调节， 并作为治疗方式。总体而言，成功完成拟议的研究将提供增强的神经胶质瘤层次结构模型，并为新型临床试验的发展提供信息。