Dynamic Complexity of Brain Tumor Stem Cells

 描述(由申请人提供)：胶质母细胞瘤是人类最致命的癌症之一，尽管进行了积极的多模式治疗。大多数癌症通过转移杀死宿主，但胶质母细胞瘤几乎普遍是致命的，因为由于扩散到正常大脑和对传统疗法的抵抗，胶质母细胞瘤没有扩散到神经轴以外。随着手术切除的改进，胶质母细胞瘤患者的寿命和生活质量得到了改善， 在放射治疗期间，改进了放射治疗和口服甲基化药物替莫唑胺，但中位生存期仍不到两年。目前的治疗方法未能延长患者生存期的原因有很多，但其中一个原因可能是肿瘤内存在复杂的异质性，这源于致癌驱动因素的异质性表达，以及与正常大脑层次结构相似的细胞层次结构，尽管存在异常的控制。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，通过肿瘤隔室的集体作用以及浸润性免疫细胞、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治疗，而免疫细胞、血管系统和反应性星形胶质细胞既可以起到肿瘤抑制因子的作用，也可以起到促进作用。正常的组织特异性干细胞由于其持续增殖的能力而构成危险。作为回应，干细胞驻留在特定的利基中，从中获得维持信号，但也限制了增殖，并在离开利基时经历分化。癌症干细胞与它们起源的器官中的干细胞共享一些细胞自主调节通路，但也重建了利基的元素。干细胞生态位是一个结构性结构，但也与氧、pH和营养可获得性的区域差异有关。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新编程代表了癌症干细胞生态位中需要控制代谢应激反应的一个因素。肿瘤的启动和维持需要异常的代谢控制。基因错乱导致肿瘤的自我更新，但细胞层次是通过核心干细胞内在转录调节、新陈代谢和利基信号之间的相互作用来维持的。我们最近证实，脑肿瘤干细胞选择在神经元中表达的高亲和力葡萄糖转运蛋白(GLUT3)来抵抗代谢应激。由于线粒体形态与谱系特征有关，我们研究了另一种对大脑代谢至关重要的机制，即线粒体动力学。在初步研究中，我们发现脑肿瘤干细胞表现出不同于非干细胞肿瘤细胞和神经前体细胞的分子调控。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了脑瘤干细胞的一个选择性脆弱点。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、调节表观遗传干细胞状态、 作为一种治疗方式。总而言之，拟议研究的成功完成将提供胶质瘤分级的增强模型，并为新的临床试验的发展提供信息。

 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.