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

基本信息

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
项目类别：
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

项目摘要

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.

总体而言：项目摘要转移性疾病是造成绝大多数癌症死亡的原因。对基本原理的理解导致转移性癌症的机制因需要复制步骤的模型而受到阻碍明智的体内转移过程，但易于严格控制并促进高分辨率、延时拍摄细胞行为的成像和定量分析。在过去的十年里，我们的团队在vivo和能够模拟转移级联的许多步骤的体外方法，包括肿瘤细胞侵袭，内渗、滞留在微循环中或粘附在血管壁上，以及外渗到血管内周围的细胞外基质。与此同时，我们开展了计算研究，提供了详细的洞察力通常无法通过实验获得。这项集体先前的工作为核心方面提供了新的线索转移过程中单细胞和集体细胞的行为，并确定了机械适应和肿瘤细胞的脆弱性有望进行针对性干预。我们提议的 U54 中心的目标是将这些已开发的测定和方法与新的测量技术相结合来询问转移生态位中的肿瘤细胞在停滞和外渗期间经历的全方位应激源，并将这些与染色质结构和肿瘤细胞转录组变化的平行研究结合起来（核心B）。这些变化对于肿瘤细胞对器官优先的机械适应至关重要转移集落的起始或向休眠的转变。我们拟议的中心的一个特点是使用国家- 最先进的体外（项目 1）和体内（项目 2）实验和计算（核心 A）来发现和探索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单独使用任何方法都无法深入了解转移性癌症，并增强我们识别的能力并筛选新疗法以抑制疾病转移性传播的趋势。