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

总体情况：项目总结 转移性疾病是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由于需要复制这一步骤的模型而受到阻碍。 在体内的明智转移过程，但服从严格控制和促进高分辨率，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， 血管内渗入，困于微循环或粘连到血管壁，以及渗入 周围的细胞外基质。与此同时，我们开发了计算研究，提供了详细的 洞察往往不可能通过实验来实现。这一集体先前的工作为中心方面提供了新的线索 转移过程中的单细胞和集体细胞行为，并确定机械适应和 肿瘤细胞的脆弱性，并有望进行有针对性的干预。我们提议的U54中心的目标是 利用这些发展起来的分析和方法，结合新的测量技术来审问 转移灶肿瘤细胞在停滞和渗出过程中所经历的应激源的全谱， 并将这些与染色质结构变化和肿瘤细胞转录组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偏好的机械适应至关重要。 转移菌落的启动或向休眠的转变。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 对转移性癌症的洞察，这是任何方法都不可能单独使用的，并增强了我们识别 并筛选新的治疗方法，以抑制疾病转移传播的趋势。

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.