Project-1: Defining the mechanisms by which neurons promote breast cancer metastasis

项目-1：定义神经元促进乳腺癌转移的机制

基本信息

批准号：
10688115
负责人：
Sohail F. Tavazoie
金额：
$ 64.07万
依托单位：
ROCKEFELLER UNIVERSITY
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：
2021-09-23 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688115
关键词：
3-Dimensional Address Affect Automobile Driving Binding Biochemical Blood Vessels Breast cancer metastasis Cell Line Cells Coculture Techniques Complex Computing Methodologies Denervation Dependence Disease Disseminated Malignant Neoplasm Distant Endothelial Cells Endothelium Extracellular Matrix Proteins Genetic Goals Image Immune Immune system Immunofluorescence Immunologic Impairment Infiltration Interdisciplinary Study Invaded Label Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Neoplasms Mechanics Mediating Molecular Molecular Probes Nature Neoplasm Metastasis Nerve Neurobiology Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurons Nonmetastatic Nutrient Oxygen Pattern Peripheral Phenotype Play Population Process Proliferating Proteins RNA-Binding Proteins Recurrence Research Resistance Risk Role Signal Transduction Skin Cancer System Testing Tumor Cell Invasion Tumor Promotion Tumor-infiltrating immune cells Work axon guidance breast cancer progression cancer cell experimental study imaging study in vivo malignant breast neoplasm malignant stomach neoplasm migration nerve supply neural neural model neuroregulation neurotransmission neurotrophic factor new therapeutic target perineural pharmacologic response single cell sequencing therapeutic target therapy resistant transcription factor tumor tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary Tumors are a heterogenous population of cancer cells, infiltrating host cells, secreted factors and extracellular matrix proteins–together comprising the tumor microenvironment. The tumor microenvironment plays profound roles in supporting tumor initiation, survival, progression and metastasis. We have discovered that tumor endothelial cells provide an “instructive” signal to cancer cells that drives metastatic progression. We found Slit2, an axon guidance molecule, to be upregulated in endothelial cells within metastatic tumors. Endothelial-specific deletion of Slit2 strongly inhibited metastasis. In a surprising discovery, we found that endothelial-Slit2 deletion also impairs tumor innervation. Nerves are only starting to be recognized as key players within the tumor stroma, with recent evidence demonstrating their requirement for tumor initiation of gastric and prostate cancers. In breast cancer, although there is some preliminary evidence that innervation correlates with tumor aggressiveness, nerve dependence for metastasis has not been explored. In this Project, we will define the role of neurons within the stroma of primary breast tumors and understand how neurons regulate metastasis. Using isogenic cell lines of differential metastatic potential, retrograde tracing and imaging studies, we will first identify neuronal sub-populations that regulate breast cancer metastasis. We will use 3D co-culture systems and in vivo denervation experiments to identify the role of neurons in tumor invasion, proliferation, local and systemic dissemination, distant seeding, and metastatic outgrowth. We will also evaluate the role of tumor innervation in therapeutic resistance in breast cancer. Next, we will use unbiased sequencing approaches to define tumor- trophic factors secreted by neurons and delineate downstream signaling axes in cancer cells. Finally, we will characterize the role of endothelial cells in guiding neurons into metastatic tumors and determine if the pro- metastatic effects of neurons are partly mediated by immune cells. The proposed inter-disciplinary research plan combines molecular, genetic, biochemical, imaging and computational approaches to establish an integrated model for neural regulation of metastatic progression by breast cancer. Collectively, these studies will define the cellular and molecular interactions between endothelial cells, neurons, and immune cells within the tumor microenvironment–an overarching goal of our proposed MetNet research center. These studies have tremendous potential for impact as that they stand to identify novel therapeutic targets that perturb neural-tumoral signaling axes driving metastasis.

项目概要肿瘤是由癌细胞、浸润宿主细胞、分泌因子和细胞外物质组成的异质群体。基质蛋白——共同构成肿瘤微环境。微环境发挥着深远的作用。我们发现，肿瘤在支持肿瘤发生、存活、进展和转移中发挥着重要作用。内皮细胞向癌细胞提供“指导性”信号，驱动转移进展。一种轴突引导分子，在内皮特异性肿瘤内的内皮细胞中上调。 Slit2 的缺失强烈抑制了转移在一个令人惊讶的发现中，我们发现内皮细胞 Slit2 的缺失。也损害肿瘤神经支配神经才刚刚开始被认为是肿瘤基质内的关键参与者，最近的证据表明它们对于胃癌和前列腺癌的肿瘤起始是必需的。乳腺癌，尽管有一些初步证据表明神经支配与肿瘤相关侵袭性、转移的神经依赖性尚未被探索。在这个项目中，我们将定义其作用。原发性乳腺肿瘤基质内的神经元，并了解神经元如何调节转移。差异转移潜能的同基因细胞系、逆行追踪和影像学研究，我们将首先鉴定我们将使用 3D 共培养系统和体内的神经元亚群。去神经实验以确定神经元在肿瘤侵袭、增殖、局部和全身中的作用我们还将评估肿瘤神经支配在传播、远处播种和转移生长中的作用。接下来，我们将使用无偏测序方法来定义肿瘤。神经元分泌的营养因子并描绘癌细胞中的下游信号轴。描述内皮细胞在引导神经元进入转移性肿瘤中的作用，并确定是否亲神经元的转移效应部分是由免疫细胞介导的。结合分子、遗传、生化、成像和计算方法来建立一个综合的总的来说，这些研究将定义乳腺癌转移进展的神经调节模型。肿瘤内内皮细胞、神经元和免疫细胞之间的细胞和分子相互作用微环境——我们提议的 MetNet 研究中心的总体目标。巨大的影响潜力，因为他们能够确定扰乱神经肿瘤的新治疗靶点信号轴驱动转移。