Neural Niche in Promoting Brain Metastatic Tumor Progression

项目摘要 标题：促进脑转移进展的神经生态位 大脑的转移进展是一个多步骤的进化过程，通过 播散性肿瘤细胞与脑微环境--“生态位”--之间的持续相互作用。尽管 控制原发肿瘤明显改善，脑转移的发生率正在增加！减少 癌症死亡率，合理设计的治疗方法，基于对肿瘤转移的机制理解 脑转移瘤患者迫切需要独特的脑转移瘤利基。大脑是什么？ 转移的利基？在大脑微环境中-利基-是无数不同类型的细胞，它们已经 推测与脑瘤和脑转移的发展有关，包括内皮细胞， 星形胶质细胞，神经干细胞/祖细胞(以下简称NSC)和日益重视的脑免疫细胞。 尽管对星形胶质细胞进行了研究，但神经干细胞及其后代对脑转移定植和 调节大脑免疫格局和转移结果尚未得到系统的研究。我们的 初步研究表明，NSC迁移到定植的肿瘤细胞，并且NSC具有功能 对于脑转移的进展是必不可少的。耐人寻味的是，神经科学领域的大量证据 提示NCS在脑部炎症过程中具有免疫抑制作用。因此，在这项提案中，我们 假设神经干细胞及其子代的脑转移倾向和潜在后果 免疫抑制活性可能有助于免疫抑制转移的利基，促进大脑 转移进展。在这项拟议的研究中，我们将使用转基因小鼠模型和最先进的 基因组学和成像方法追踪和分析高度异质性细胞类型参与的作用 神经干细胞分化和免疫抑制及其在调节脑转移生长中的作用。这 整合多学科专业知识的协作努力，包括癌症生物学、神经科学、 计算生物学，使我们能够：1)检查和追踪神经干细胞对脑转移的分化反应 在表型水平上；2)可视化和定量测量脑转移瘤巢细胞的行为 以及它们转录组的异质性；3)研究神经干细胞分化的机制 促进脑转移的进展。通过基础和预案获得新的深入的机械论见解 临床创新研究将为未来脑转移瘤的治疗铺平道路。

Project Summary Title: Neural Niche in Promoting Brain Metastasis Progression Metastatic progression at the brain is a multi-step, evolutionary process that is accomplished through a consistent interplay between disseminated tumor cells and brain microenvironment - "the niche". Despite significantly improved control of primary tumors, the incidence of brain metastasis is increasing! To reduce cancer mortality, rationally-designed therapeutics, based on a mechanistic understanding of metastasis in at the unique brain metastatic niche, are urgently needed for brain metastasis patients. What's the brain metastatic niche? In the brain microenvironment - the niche - is a myriad of diverse cell types that have been speculated to contribute to the brain tumor and brain metastasis development, including endothelial cells, astrocytes, neural stem/progenitor cells (NSC hereafter) and increasingly appreciated brain immune cells. Despite studies of astrocytes, how do the NSC and its progenies respond to brain metastatic colonization and regulate brain immune landscape and the metastatic outcome has yet to be systematically investigated. Our preliminary studies have demonstrated that NSC migrates to colonized tumor cells and NSC is functionally essential for brain metastasis progression. Intriguingly, ample evidence from in the field of neuroscience suggests an immune suppressive role of NCS during the brain inflammation. Thus, in this proposal, we hypothesize that NSC and its progenies' brain metastasis tropism and potentially consequential immunosuppressive activity could contribute to an immune-suppressive metastatic niche, facilitating brain metastasis progression. In this proposed study, we will use transgenic mouse models and state-of-the-art genomics and imaging approach to trace and analyze the role of highly heterogeneous cell types involved in NSC differentiation and immune suppression and their roles in regulating brain metastatic outgrowth. This collaborative effort integrating multidisciplinary expertise, including cancer biology, neuroscience, computational biology, allow us to: 1) examine and trace the NSC differentiation response to brain metastasis at the phenotypical level; 2) visualize and quantitatively measure the behavior of brain metastatic niche cells and their transcriptome heterogeneity; 3) examine the mechanism by which neural cells derived from NSC promotes brain metastasis progression. New in-depth mechanistic insights obtained through basic and pre- clinical innovative research will pave the way to future brain metastases treatments.