Neural Niche in Promoting Brain Metastatic Tumor Progression

促进脑转移瘤进展的神经生态位

基本信息

批准号：
10636336
负责人：
Siyuan Zhang
金额：
$ 47.98万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636336
关键词：
3-Dimensional Adjuvant Therapy Astrocytes Basic Science Behavior Brain Brain Neoplasms Cancer Biology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Computational Biology Consequentialism Development Encephalitis Endothelial Cells Evolution Future Genetic Genetic Variation Genomic approach Heterogeneity Image Analysis Immune Immune system Immunosuppression In Situ Incidence Infiltration Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Metastatic malignant neoplasm to brain Metastatic to Molecular Neoplasm Metastasis Neurons Neurosciences Organ Outcome Patients Phenotype Plant Roots Preclinical Testing Primary Neoplasm Process Regulation Research Resolution Role Signal Transduction Spatial Distribution Therapeutic Three-Dimensional Image Tissue Sample Tissue imaging Transforming Growth Factor beta Transgenic Mice Tropism base brain cell cell type clinical practice imaging approach improved in vivo inhibitor innovation insight interdisciplinary approach mortality mouse model multidisciplinary neoplastic cell neuroinflammation novel pre-clinical pre-clinical research prevent rational design relating to nervous system response single cell analysis single cell sequencing single-cell RNA sequencing spatial relationship spatiotemporal stem stem cells targeted treatment transcriptome transcriptomics tumor tumor progression

项目摘要

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.

项目概要标题：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大脑微环境（“利基”）之间一致的相互作用。尽管原发肿瘤控制明显改善，脑转移发生率却在增加！减少癌症死亡率，合理设计的治疗方法，基于对癌症转移的机制理解独特的脑转移微环境，是脑转移患者迫切需要的。大脑是什么转移性利基？在大脑微环境（生态位）中存在着无数不同的细胞类型，这些细胞类型已被据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/祖细胞（以下简称 NSC）和日益受到重视的脑免疫细胞。尽管对星形胶质细胞进行了研究，但 NSC 及其后代如何响应脑转移定植和调节大脑免疫景观和转移结果尚未得到系统研究。我们的初步研究表明，NSC 能够迁移至定植的肿瘤细胞，并且 NSC 具有功能性对于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 在脑部炎症期间具有免疫抑制作用。因此，在本提案中，我们假设 NSC 及其后代的脑转移倾向和潜在的后果免疫抑制活性可能有助于形成免疫抑制转移生态位，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参与的高度异质细胞类型的作用 NSC 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 NSC 分化对脑转移的反应在表型水平； 2）可视化并定量测量脑转移微环境细胞的行为及其转录组异质性； 3）研究NSC衍生神经细胞的机制促进脑转移进展。通过基础和预习获得新的深入机制见解临床创新研究将为未来脑转移治疗铺平道路。