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：
10675623
负责人：
Siyuan Zhang
金额：
$ 46.37万
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/10675623
关键词：
Adjuvant Therapy Astrocytes Basic Science Behavior Brain Brain Neoplasms Cancer Biology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Computational Biology 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 Maps Measures Mediating Metastatic malignant neoplasm to brain Molecular Neoplasm Metastasis Neurons Neurosciences Organ Outcome Patients Phenotype 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 Visualization brain cell brain shape cell type clinical practice imaging approach improved in vivo inhibitor innovation insight interdisciplinary approach migration mortality mouse model multidisciplinary neoplastic cell nerve stem cell neural neuroinflammation novel pre-clinical pre-clinical research prevent rational design response single cell analysis single cell sequencing single-cell RNA sequencing spatial relationship spatiotemporal targeted treatment three-dimensional visualization transcriptome transcriptomics tumor tumor progression validation studies

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.

项目摘要标题：促进脑转移进展的神经利基市场大脑的转移进展是一个多步进的进化过程，可以通过散布肿瘤细胞和脑微环境之间的一致相互作用 - “利基”。尽管大脑转移的发生率正在显着改善对原发性肿瘤的控制，这正在增加！减少癌症死亡率，合理设计的治疗剂，基于对AT转移的机械理解脑转移患者迫切需要独特的脑转移生态位。什么是大脑转移性利基？在大脑微环境中 - 利基 - 是多种多样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，神经茎/祖细胞（NSC）以及越来越多的脑免疫细胞。尽管研究了星形胶质细胞，但NSC及其后代如何应对脑转移定植和调节大脑免疫景观和转移结果尚未系统地研究。我们的初步研究表明，NSC迁移到定殖的肿瘤细胞，NSC在功能上是对于脑转移的进展至关重要。有趣的是，来自神经科学领域的充分证据提示NC在脑部炎症过程中的免疫抑制作用。因此，在此提案中，我们假设NSC及其后代的大脑转移疗法和潜在的结果免疫抑制活性可能有助于免疫抑制转移性利基市场，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，用于追踪和分析与高度异构细胞类型的作用 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，允许我们：1）检查和追踪NSC分化对脑转移的反应在表型级别； 2）可视化和定量测量脑转移性细胞的行为以及他们的转录组异质性； 3）检查神经细胞从NSC衍生的机制促进脑转移进展。通过基本和预先获得的新的深入的内在机械见解临床创新研究将为未来的脑转移治疗铺平道路。