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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.

项目总结