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

总体：项目总结 转移性疾病是造成绝大多数癌症死亡的原因。理解基本的 导致转移性癌症的机制受到了需要复制该步骤的模型的阻碍， 明智的转移过程中，体内，但服从严格控制，并促进高分辨率，时间推移 细胞行为的成像和定量分析。在过去的十年里，我们的团队在体内开发了 能够模拟包括肿瘤细胞侵袭在内的转移级联的许多步骤的体外方法， 内渗、微循环中的捕获或与血管壁的粘附，以及外渗到微循环中。 周围的细胞外基质。与此同时，我们已经开发了计算研究，提供了详细的 通过实验往往无法获得洞察力。这一集体先前的工作已经揭示了新的中心方面 转移过程中的单细胞和集体细胞行为，并确定了机械适应， 肿瘤细胞的脆弱性，有希望进行有针对性的干预。我们建议的U 54中心的目标是 为了将这些开发的测定和方法与新的测量技术相结合， 肿瘤细胞在转移小生境中在停滞和外渗期间经历的全部应激源， 并将其与肿瘤细胞染色质结构和转录组变化的平行研究相结合 (Core B）。这些变化对于肿瘤细胞朝向器官优先的机械适应是至关重要的。 转移集落的开始或向休眠的过渡。我们提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），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 深入了解转移性癌症，不可能通过单独使用任何方法，并提高我们的能力， 并筛选新的治疗方法来抑制疾病转移扩散的趋势。

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.