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

• 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
• 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

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.

项目摘要 肿瘤是癌细胞，浸润宿主细胞，分泌因子和细胞外的异质种群 基质蛋白 - 结合完成肿瘤微环境。肿瘤微环境发挥着深刻的作用 在支持肿瘤倡议，生存，进展和转移中的作用。我们发现肿瘤 内皮细胞为癌细胞提供了“启发性”信号，从而驱动转移性进展。我们找到了slit2， 轴突引导分子，将在转移性肿瘤内的内皮细胞中进行更新。内皮特异性 SLIT2的缺失强烈抑制转移。在一个令人惊讶的发现中，我们发现内皮slit2删除 还会损害肿瘤神经。神经刚刚开始被认为是肿瘤基质中的关键参与者， 最近有证据表明他们对胃癌和前列腺癌的肿瘤开始的要求。在 乳腺癌，尽管有一些初步证据表明神经与肿瘤相关 尚未探索侵略性，神经依赖性。在这个项目中，我们将定义角色 原发性乳腺肿瘤基质内神经元的神经元，并了解神经元如何调节转移。使用 具有差异转移潜力，逆行追踪和成像研究的同源细胞系，我们将首先识别 调节乳腺癌转移的神经元亚群。我们将使用3D共培养系统和体内 神经元在肿瘤侵袭，增殖，局部和全身性的神经元中的作用 传播，分离播种和转移性产物。我们还将评估肿瘤神经在 乳腺癌的治疗性。接下来，我们将使用公正的测序方法来定义肿瘤 神经元和描绘癌细胞中下游信号轴的营养因子。最后，我们会的 表征内皮细胞在引导神经元转移性肿瘤中的作用，并确定是否促进 神经元的转移作用部分由免疫细胞介导。拟议的跨学科研究计划 结合分子，遗传，生化，成像和计算方法以建立综合的 乳腺癌转移性进展的神经调节模型。总的来说，这些研究将定义 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 - 我们拟议的Metnet研究中心的总体目标。这些研究有 影响力的巨大潜力是确定扰动神经肿瘤的新型治疗靶标 信号轴驱动转移。