Project 1 Mouse Models Analysis

项目1 小鼠模型分析

基本信息

批准号：
10729466
负责人：
EDGAR G. ENGLEMAN
金额：
$ 56.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729466
关键词：
Adaptive Immune System Algorithms Anatomy Architecture Atypical lymphocyte Automobile Driving Back Biological Markers Blocking Antibodies Cell Communication Cells Chronology Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Computing Methodologies Cytometry Data Development Diagnosis Disease Disease Progression Distal Distant Distant Metastasis Education Flow Cytometry Gene Expression Profile Genes Genetic Transcription Head and Neck Cancer Human Image Immune Immune Evasion Immune Tolerance Kinetics Knockout Mice Label Leukocyte Trafficking Leukocytes Lymph Node Involvement Lymphatic Malignant Neoplasms Mediating Metastatic Neoplasm to Lymph Nodes Modeling Mus Nature Neighborhoods Neoplasm Metastasis Nodal Non-Small-Cell Lung Carcinoma Patients Population Predisposition Prevention Primary Neoplasm Process Property Regulatory T-Lymphocyte Role Site Solid Stromal Cells Study models Systems Biology Tissues Tumor Biology Tumor Promotion Tumor-infiltrating immune cells cancer cell conditioning cytokine data integration high dimensionality imaging platform implantation lymph nodes markov model migration mouse model neoplastic cell new therapeutic target novel prevent programs single-cell RNA sequencing therapy design trafficking transcriptomics tumor

项目摘要

SUMMARY/ABSTRACT: PROJECT 1 Lymph node (LN) metastasis precedes further dissemination for most solid malignancies and confers a stage III diagnosis. Nonetheless, the mechanistic role of LN metastasis in further disease progression is poorly understood. We discovered in mice that in colonizing LNs, tumor cells activate transcriptional programs that enable their induction of tumor-specific immune tolerance through interactions with LN leukocytes. These leukocytes subsequently recirculate throughout the host, resulting in systemic immune tolerance facilitating metastatic seeding of distant sites. Importantly, we found the same conserved transcriptional signature in LN metastases in humans, suggesting that the mechanisms driving LN metastasis and immune tolerance in our mouse model are pertinent to human cancers. We hypothesize that local interactions between tumor cells, leukocytes, and stroma within LNs before, during, and following LN colonization alter distant tissues to promote disease progression. We expect these interactions to involve homotypic and heterotypic cell-cell interactions, orchestration of architectural changes within LNs, tumors, and distant sites, and trafficking of various populations throughout the host. We will use syngeneic mouse models to identify the mechanisms by which these interactions facilitate disease progression through the following approaches. 1: Determine the kinetics by which tumors generate systemic immune tolerance. Using a high-dimensional imaging platform (CODEX), we will uncover longitudinal changes in local microenvironments across the host. 2: Interrogate the nature of heterotypic cell-cell interactions within LNs and the mechanisms by which these interactions facilitate immune evasion and induction of immune tolerance. We will use scRNA-seq to identify transcriptional changes in immune and stromal populations interacting with malignant cells within LNs. Using spatial transcriptomics, we will determine how the gene expression patterns of cells interacting with malignant cells differ from those at a distance. To confirm the functional significance of these targets identified and those identified in Project 2, we will combine CRISPR- mediated gene editing of LN metastatic tumors, along with cell depletion studies and knockout mice or inducible mouse models. 3: Determine how trafficking of immune cells from tumor-involved LNs establish a pro-metastatic microenvironment at distant sites. We will employ a novel cell labeling platform to evaluate trafficking of leukocytes and stromal cells from tumor-involved LNs to distant sites and back to the primary tumor. These studies will reveal the mechanisms whereby LN metastases promote tumor spread to distant sites and identify novel targets for the prevention and treatment of metastatic disease.

摘要/摘要：项目1 淋巴结（LN）转移先于大多数固体恶性肿瘤的进一步传播，并赋予III期诊断。但是，LN转移在进一步疾病进展中的机理作用很差理解。我们在小鼠中发现在殖民LN中，肿瘤细胞激活转录程序通过与LN白细胞相互作用，使它们能够诱导肿瘤特异性免疫耐受性。这些白细胞随后在整个宿主中再循环，导致全身免疫耐受性促进遥远位点的转移播。重要的是，我们在LN中发现了相同的保守转录签名人类转移，表明我们的机制驱动LN转移和免疫耐受性小鼠模型与人类癌症有关。我们假设肿瘤细胞之间的局部相互作用，在LN结构化之前，期间和之后的LN中的白细胞和基质改变远处的组织以促进疾病进展。我们期望这些相互作用涉及同型和异型细胞 - 细胞相互作用， LN，肿瘤和远处的建筑变化的管弦乐，以及各种人口的贩运在整个主机中。我们将使用合成鼠标模型来识别这些相互作用的机制通过以下方法促进疾病进展。 1：确定肿瘤的动力学产生系统性免疫耐受性。使用高维成像平台（codex），我们将发现整个宿主的局部微环境的纵向变化。 2：询问异型细胞细胞的性质 LN中的相互作用以及这些相互作用促进免疫逃避和诱导的机制免疫耐受性。我们将使用SCRNA-SEQ识别免疫和基质的转录变化种群与LNS中的恶性细胞相互作用。使用空间转录组学，我们将确定与恶性细胞相互作用的细胞的基因表达模式与距离的基因表达模式不同。确认这些目标的功能意义以及项目2中确定的目标，我们将结合CRISPR- LN转移性肿瘤的介导基因编辑，以及细胞耗竭研究和敲除小鼠或诱导鼠标模型。 3：确定如何从肿瘤涉及的LN进行免疫细胞的运输建立促近代远处的微环境。我们将采用一个新颖的细胞标签平台来评估贩运白细胞和基质细胞从肿瘤涉及的LN到遥远的部位并回到原发性肿瘤。这些研究将揭示LN转移酶促进肿瘤扩散到远处的机制并确定预防和治疗转移性疾病的新目标。