Neural Niche in Promoting Brain Metastatic Tumor Progression

促进脑转移瘤进展的神经生态位

• 批准号: 10298995
• 负责人: Siyuan Zhang
• 金额: $ 47.17万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10298995
• 关键词: Adjuvant; Astrocytes; Basic Science; Behavior; Brain; Brain Neoplasms; Cancer Biology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Complement 1q; Computational Biology; Consequentialism; Development; Encephalitis; Endothelial Cells; Evolution; Future; Genetic; Genetic Models; Genetic Variation; Genomic approach; Heterogeneity; Image Analysis; Immune; Immune system; Immunosuppression; In Situ; Incidence; Malignant Neoplasms; Measures; Metastatic malignant neoplasm to brain; Modeling; Molecular; Neoplasm Metastasis; Neurons; Neurosciences; Organ; Outcome; Patients; Phenotype; Primary Neoplasm; Process; Research; Resolution; Role; Signal Transduction; Testing; Therapeutic; Three-Dimensional Image; Tissue Sample; Tissue imaging; Transforming Growth Factor beta; Transgenic Mice; Treatment Protocols; Tropism; base; cell type; clinical practice; design; imaging approach; improved; innovation; insight; interdisciplinary approach; migration; mortality; mouse model; multidisciplinary; neoplastic cell; novel; pre-clinical; pre-clinical research; prevent; relating to nervous system; response; single cell analysis; single-cell RNA sequencing; spatiotemporal; stem; stem cells; targeted treatment; therapy design; tissue resource; transcriptome; tumor; tumor progression

Project Summary Title: Neural Niche in Promoting Brain Metastatic Tumor 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.

项目摘要 标题：神经生态位促进脑转移瘤进展 脑转移性进展是一个多步骤的进化过程， 扩散的肿瘤细胞和脑微环境之间的一致相互作用-“小生境”。尽管 原发肿瘤控制明显提高，脑转移的发病率也在增加！减少 癌症死亡率，合理设计的治疗方法，基于对转移的机械理解， 独特的脑转移瘤小生境，是脑转移患者急需的。什么是大脑 转移性小生境？在大脑微环境中--生态位--是无数不同的细胞类型， 推测有助于脑肿瘤和脑转移的发展，包括内皮细胞， 星形胶质细胞、神经干细胞/祖细胞（下文称为NSC）和日益受到重视的脑免疫细胞。 尽管有星形胶质细胞的研究，但NSC及其后代如何对脑转移性定植做出反应， 调节脑免疫景观和转移的结果还有待系统研究。我们 初步研究表明，NSC迁移到定殖的肿瘤细胞，并且NSC在功能上是 对脑转移进展至关重要。有趣的是，来自神经科学领域的大量证据 表明NCS在脑炎症过程中具有免疫抑制作用。因此，在本提案中，我们 假设NSC及其后代具有脑转移倾向， 免疫抑制活性可能有助于免疫抑制转移小生境， 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来追踪和分析参与的高度异质性细胞类型的作用， 神经干细胞分化和免疫抑制及其在脑转移瘤生长中的作用。这 协作努力整合多学科的专业知识，包括癌症生物学，神经科学， 计算生物学，使我们能够：1）检查和跟踪NSC分化对脑转移的反应 在表型水平上; 2）可视化并定量测量脑转移瘤小生境细胞的行为 以及它们的转录组异质性; 3）研究神经干细胞来源于神经干细胞的机制， 促进脑转移进展。新的深入的机械见解，通过基本的和预- 临床创新研究将为未来的脑转移治疗铺平道路。