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.

项目总结/摘要 癌症相关成纤维细胞（CAFs）和细胞外微环境（ECM）在癌症中的作用 转移已经变得越来越受重视。肿瘤微环境由多种 隔室：细胞的、物理的和化学的。癌组织中的每个隔室与 正常组织，但每一个在转移中发挥的作用以及它们如何相互影响还知之甚少。 CAF已被证明部分通过改变局部胶原蛋白来促进肿瘤细胞转移 微环境CAF可以通过3种方式增强癌症转移：（1）CAF与肿瘤转移的直接相关性。 肿瘤内的前导细胞，（2）局部微环境的CAF机械改变，以及（3）CAF 这些分泌物可以发出肿瘤转移和胶原重塑的信号。化学机械反馈 CAF、癌细胞和ECM之间的关系仍然知之甚少。在这里，我们的目标是阐明 CAF对前导细胞的化学机械反馈功能以及促进CAF的微环境。 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)研究CAF分泌体对局部胶原结构和功能的影响。我们将 结合原发性乳腺肿瘤类器官利用基于微流体细胞的侵袭测定，或 重建的乳腺肿瘤类器官（与分离的前导细胞或CAF混合的非迁移性乳腺细胞） 探索CAF对集体细胞迁移的影响。我们将孤立的作用产生的机械力 肿瘤内CAF对前导细胞功能的影响以及CAF产生的力对胶原蛋白的影响 变形和重塑（1）。然后，我们将比较CAF对集体迁移的机械效应， 化学CAF分泌物对胶原重塑的影响（2）。我们的目标是量化两者的相对作用 机械和化学模型，以产生CAF功能对集体细胞迁移的预测模型。 我们将通过使用工程技术来操纵微环境并观察 对集体移民的影响。我们将联合收割机与生物技术相结合， 和前导细胞来识别CAF如何能够影响集体细胞迁移。