Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth

器官选择性转移定植、休眠和生长的机械决定因素

• 批准号: 10271565
• 负责人: ROGER D KAMM
• 金额: $ 154.3万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271565
• 关键词: 3-Dimensional; Address; Adhesions; Adhesives; Affect; Basement membrane; Biological Assay; Blood Circulation; Blood Platelets; Breast Melanoma; Cell Death; Cell Survival; Cells; Cessation of life; Chromatin; Chromatin Structure; Complex; Computer Analysis; Dermis; Disease; Disseminated Malignant Neoplasm; Endothelium; Environment; Extracellular Matrix; Extravasation; Fibrin; Gene Expression; Genomics; Goals; Image; In Vitro; Individual; Intervention; Light; Liver; Malignant Neoplasms; Measurement; Mechanics; Metastatic to; Methods; Microcirculation; Modeling; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Nuclear; Organ; Organ Specificity; Pathway interactions; Phenotype; Primary Neoplasm; Probability; Process; Property; Resolution; Role; Site; Stress; Techniques; Technology; Therapeutic; Thrombus; Time; Tissues; Tumor Cell Invasion; Vision; Work; cell behavior; cell type; computer studies; experience; experimental study; hemodynamics; in vitro Model; in vivo; insight; intravital imaging; metastatic process; migration; monolayer; mortality; neoplastic cell; novel therapeutics; prevent; programs; response; shear stress; stressor; transcriptome; transcriptomics; triple-negative invasive breast carcinoma

Overall: PROJECT SUMMARY Metastatic disease is responsible for the vast majority of cancer mortality. Understanding of the fundamental mechanisms leading to metastatic cancer has been hampered by the need for models that replicate the step- wise metastatic process in vivo, yet are amenable to tight control and facilitate high-resolution, time-lapse imaging and quantitative analysis of cell behavior. Over the past decade, our team has developed in vivo and in vitro methods capable of simulating many steps of the metastatic cascade including tumor cell invasion, intravasation, trapping in the microcirculation or adhesion to the vessel walls, and extravasation into the surrounding extracellular matrix. In parallel, we have developed computational studies that provided detailed insights often not possible through experiments. This collective prior work has shed new light on central aspects of single-cell and collective cell behavior during metastasis, and identified mechanical adaptations and vulnerabilities of the tumor cell with promise for targeted interventions. The goal of our proposed U54 Center is to employ these developed assays and methods in combination with new measurement techniques to interrogate the full spectrum of stressors experienced by tumor cells in the metastatic niche during arrest and extravasation, and couple these with parallel studies of changes in chromatin structure and the transcriptome of tumor cells (Core B). These changes are critical to mechano-adaptation of the tumor cells towards an organ-preferential initiation of a metastatic colony or transition to dormancy. A hallmark of our proposed center is the use of state- of-the-art in vitro (Project 1) and in vivo (Project 2) experiments and computation (Core A) to uncover and probe the factors that ultimately determine tumor cell fate. We anticipate that such integrated studies will provide new insights into metastatic cancer, not possible by the use of any method alone, and enhance our ability to identify and screen for new therapies to inhibit the tendency for metastatic spread of disease.

总体：项目摘要 转移性疾病是绝大多数癌症死亡率的原因。理解基本 导致转移性癌症的机制受到复制的模型的需求受到阻碍 在体内明智的转移过程，但可以进行严格的控制和促进高分辨率，延时 细胞行为的成像和定量分析。在过去的十年中，我们的团队在体内发展了 体外方法能够模拟转移性级联反应的许多步骤，包括肿瘤细胞侵袭， 弹药，捕获微循环或对血管壁的粘附，然后渗入 周围细胞外基质。同时，我们开发了计算研究，提供了详细的 通过实验通常无法进行见解。这项集体先前的工作为中心方面提供了新的启示 转移过程中的单细胞和集体细胞行为，并确定了机械适应和 肿瘤细胞的脆弱性，有望进行靶向干预措施。我们建议的U54中心的目标是 使用这些开发的测定和方法结合新的测量技术来审问 肿瘤细胞在逮捕和渗出过程中肿瘤细胞经历的全部压力源， 并将这些与染色质结构变化和肿瘤细胞的转录组的变化相关研究 （核心B）。这些变化对于肿瘤细胞向器官推荐的机械适应至关重要 启动转移菌落或向休眠过渡。我们拟议中心的标志是使用国家 - 体外的艺术（项目1）和体内（项目2）实验和计算（核心A）以揭示和探测 最终决定肿瘤细胞命运的因素。我们预计这种综合研究将提供新的 对转移性癌症的见解，仅通过使用任何方法，并增强了我们识别的能力 并筛选了新疗法，以抑制疾病转移性传播的趋势。