Metastasis and biophysics of clusters of circulating tumor cells in the microcirculation

摘要 当循环中的肿瘤细胞从原发肿瘤转移到远处的器官时，它们通过 发行量。循环中的肿瘤细胞多细胞团虽然在血液中较少见，但 与单个循环肿瘤细胞和肿瘤的存在相比，更有可能建立转移 血液中的聚集性与患者的预后显著恶化有关。尽管有 对于它们更大的转移潜能，许多可疑的解释仍然是未知的 丛生行为，尤指在身体狭窄的血管中。最近的证据表明， 集群在穿越狭窄的过程中，经历了结构和组织的动态变化。 微循环中的力量导致集群可逆地重新组织成单文件链，以实现 穿过狭窄的毛细血管和核膜破裂并迅速修复 在迁徙过程中通过狭窄的狭窄。星团内的两个生物物理参数， 细胞黏附强度和核力学对这些行为至关重要。因为重要的是 这些参数在转移进展的许多方面所起的作用，我们假设这些 参数调节微循环中团簇对物理力的生物物理反应，以及 这些相互作用在集群的竞争优势中发挥着重要作用 用于播种转移的单个癌细胞。为此，我们提出了三个具体目标。在目标1中，我们 将开发具有圆形内皮网络的下一代人类微循环模型 细胞涂层微流控器件与几何形状匹配的计算模拟。在目标2中，我们将 探讨细胞间黏附如何影响肿瘤的生物物理反应和转移形成能力 通过使用我们开发的微循环中的均质与非均质集群 模特们。最后，在目标3中，我们将研究核膜破裂的物理基础，DNA损伤， 遗传不稳定和其他DNA水平的影响，涉及转移进展。理解 微循环中团簇的生物物理学和生物学之间的相互作用将被阐明 可用于对抗集群引发的转移的进展的机制。

ABSTRACT Circulating tumor cells drive metastasis when they travel from primary tumors to distant organs via the circulation. Multicellular clusters of circulating tumor cells though less frequently observed in blood, are much more likely to establish metastases than individual circulating tumor cells and the presence of tumor clusters in blood has been associated with dramatically worse prognoses in patients. Although there are many suspected explanations for their greater metastatic potentials, much is still unknown about the behavior of clusters, especially in the narrow vessels of the body. Recent evidence has demonstrated that cluster transiting through narrow constrictions experience dynamic changes to structure and organization. Forces in the microcirculation cause clusters to reversibly re-organize into single-file chains to enable transit through narrow capillary-sized vessels and nuclear envelopes are ruptured and rapidly repaired during migration events through narrow constrictions. Two biophysical parameters within clusters, cellular adhesion strengths and nuclear mechanics, are vital for these behaviors. Because of the important role that these parameters play in many aspects of metastatic progression, we hypothesize that these parameters modulate the biophysical responses of clusters to physical forces in the microcirculation, and that these interactions play a significant role in the competitive edge that clusters have edge over individual cancer cells for seeding metastases. To this end, we propose three specific aims. In aim 1, we will develop next generation models of the human microcirculation with rounded networks of endothelial cell coated microfluidic devices and geometry matched computational simulations. In aim 2, we will explore how intercellular adhesions affect the biophysical responses and metastasis-forming abilities of homogeneous versus heterogeneous clusters in the microcirculation through the use of our developed models. Finally, in aim 3 we will study the physical basis for nuclear envelope rupture, DNA-damage, genetic instability and other DNA-level affects that are involved in metastatic progression. Understanding the interplay between the biophysics and biology of clusters within the microcirculation will elucidate mechanisms that can be used to combat the progression of cluster-initiated metastases.