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

摘要 当循环肿瘤细胞从原发性肿瘤通过淋巴结转移到远处器官时， 流通循环肿瘤细胞的多细胞簇虽然在血液中不太常见，但也是常见的。 比单个循环肿瘤细胞更有可能建立转移， 血液中的聚集物与患者的严重疾病有关。虽然有 许多怀疑的解释，他们更大的转移潜力，很多仍然是未知的， 集群的行为，特别是在身体的狭窄血管。最近的证据表明， 集群通过狭窄的约束过渡，经历结构和组织的动态变化。 微循环中的力导致簇可逆地重新组织成单列链， 通过狭窄的毛细血管和核膜的运输破裂并迅速修复 通过狭窄的收缩。两个生物物理参数在集群内， 细胞粘附强度和核力学对这些行为至关重要。因为重要的 这些参数在转移进展的许多方面发挥作用，我们假设这些参数 参数调节簇对微循环中的物理力的生物物理响应，以及 这些相互作用在集群的竞争优势中发挥着重要作用 用于接种转移的单个癌细胞。为此，我们提出三个具体目标。在目标1中，我们 将开发下一代人类微循环模型， 细胞涂覆的微流体装置和几何形状匹配的计算模拟。在目标2中，我们将 探索细胞间粘附如何影响生物物理反应和转移形成能力， 均匀与异质集群的微循环，通过使用我们开发的 模型最后，在目标3中，我们将研究核膜破裂，DNA损伤， 遗传不稳定性和其他DNA水平的影响，参与转移进展。理解 微循环中的生物物理学和生物学之间的相互作用将阐明 这些机制可用于对抗集群引发的转移的进展。

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.