Chemo-Mechanical Feedback between CAFs, Leader Cells, and the Extracellular Microenvironment Regulates Leader Cell Regulated Collective Cell Migration

CAF、前导细胞和细胞外微环境之间的化学机械反馈调节前导细胞调节集体细胞迁移

• 批准号: 10537168
• 负责人: Vasilios Aris Morikis
• 金额: $ 6.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537168
• 关键词: 3-Dimensional; Adhesions; Affect; American; Attention; Biochemical; Biological; Biological Assay; Biological Process; Biomechanics; Breast Cancer Cell; Breast cancer metastasis; Cancerous; Cell Adhesion; Cell physiology; Cells; Cessation of life; Chemical Models; Chemicals; Collagen; Collagen Fiber; Collagen Receptors; Coupled; Coupling; Data; Devices; Diagnosis; Engineering; Environment; Experimental Designs; Extracellular Matrix; Feedback; Fibrillar Collagen; Fibroblasts; Goals; Heterogeneity; Human; Image; Integrin Binding; Lab-On-A-Chips; Malignant Neoplasms; Mammary Neoplasms; Measures; Mechanics; Metastatic breast cancer; Microfluidic Microchips; Microfluidics; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Organ; Organoids; Play; Predictive Cancer Model; Primary Neoplasm; Proteomics; Recombinant Proteins; Research Proposals; Role; Signal Transduction; Stromal Cells; Stromal Neoplasm; Structure; Techniques; Testing; Tissues; Tumor Cell Invasion; Tumor Cell Line; United States; Woman; adhesion receptor; base; cancer cell; cancer diagnosis; cancer therapy; cell motility; design; discoidin receptor; extracellular; flexibility; genetic manipulation; in vivo; ineffective therapies; live cell imaging; malignant breast neoplasm; mammary; mechanical force; mechanical signal; migration; mortality; neoplastic cell; novel; prevent; reconstitution; second harmonic; single-cell RNA sequencing; targeted cancer therapy; therapeutic target; translational impact; tumor; tumor microenvironment

Project Summary/Abstract The impact of cancer associated fibroblasts (CAFs) and the extracellular microenvironment (ECM) in cancer metastasis has become more and more appreciated. The tumor microenvironment consists of multiple compartments: cellular, physical, and chemical. Each compartment in cancerous tissues differs greatly from normal tissue, yet the role that each plays in metastasis and how they affect each other is poorly understood. CAFs have been shown to promote tumor cell metastasis in part by altering the local collagen microenvironment. CAFs can enhance cancer metastasis in 3 ways; (1) direct association between CAFs and leader cells within the tumor, (2) CAF mechanical alterations of the local microenvironment, and (3) CAF secretions that can signal for tumor metastasis and collagen remodeling. How the chemo-mechanical feedback between CAFs, cancer cells, and the ECM remains poorly understood. Here, our goal is to elucidate the chemo-mechanical feedback function of CAFs on leader cells and the microenvironment that facilitates directed collective cell migration. (1) Quantify the impact of CAFs on collective cell migration and ECM remodeling. (2) To examine the effect of the CAF secretome on local collagen structure and function. We will utilize microfluidic cell-based invasion assays in conjunction with primary breast tumor organoids or reconstituted breast tumor organoids (non-migratory mammary cells mixed with isolated leader cells or CAFs) to probe the effect of CAFs on collective cell migration. We will isolate the role of mechanical forces generated by CAFs within the tumor on leader cell function and the effect of CAF generated forces on collagen deformation and remodeling (1). We will then compare the mechanical effect of CAFs on collective migration to that of the chemical CAF secretions on collagen remodeling (2). We aim to quantify the relative role of both mechanical and chemical models to generate a predictive model of CAF function on collective cell migration. We will verify this model by using engineering techniques to manipulate the microenvironment and observe the effect on collective migration. We will combine this with biological techniques to genetically manipulate CAFs and leader cells to identify how CAFs are capable of effecting collective cell migration.

项目摘要/摘要 癌症相关成纤维细胞（CAF）和细胞外微环境（ECM）的影响在癌症中 转移变得越来越受到赞赏。肿瘤微环境由多个 隔室：细胞，物理和化学。癌组织中的每个隔室都与 正常的组织，但是每个人在转移中的作用及其如何影响彼此。 CAF已被证明可以通过改变局部胶原蛋白来部分促进肿瘤细胞转移 微环境。 CAF可以通过三种方式增强癌症转移。 （1）CAFS和 肿瘤内的领导细胞，（2）局部微环境的CAF机械改变，（3）CAF 可以信号的肿瘤转移和胶原蛋白重塑的分泌物。化学机械反馈如何 在CAF，癌细胞和ECM之间的理解周密。在这里，我们的目标是阐明 CAF在领导者细胞和促进的微环境上的化学机械反馈功能 定向集体细胞迁移。 （1）量化CAF对集体细胞迁移和ECM的影响 重塑。 （2）检查CAF分泌组对局部胶原蛋白结构和功能的影响。我们将 利用基于微流体细胞的浸润测定法与原发性乳腺肿瘤器官或 重建的乳腺肿瘤器官（非迁移乳细胞与孤立的领导者或CAF混合） 探测CAF对集体细胞迁移的影响。我们将隔离产生的机械力的作用 肿瘤内的CAF对领导者细胞功能以及CAF产生的对胶原蛋白的影响 变形和重塑（1）。然后，我们将比较CAF对集体迁移到的机械效应 胶原蛋白重塑的化学CAF分泌物（2）。我们旨在量化两者的相对作用 机械和化学模型以在集体细胞迁移中生成CAF功能的预测模型。 我们将通过使用工程技术来操纵微环境并观察到该模型 对集体迁移的影响。我们将将其与生物技术结合起来，以操纵CAF 和领导细胞以确定CAF如何影响集体细胞迁移。