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

微循环中循环肿瘤细胞簇的转移和生物物理学

• 批准号: 9924267
• 负责人: Daniel A. Haber
• 金额: $ 60.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-08 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924267
• 关键词: Adhesions; Affect; Behavior; Biological; Biological Models; Biology; Biomechanics; Biophysics; Blood; Blood Circulation; Blood capillaries; Blood flow; Breast; Caliber; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Culture Techniques; Cell Nucleus; Cell-Matrix Junction; Cells; Clinical; Computer Models; Computer Simulation; DNA; DNA Damage; Distant; Endothelial Cells; Epithelial; Epithelium; Event; Fibroblasts; Genetic; Genomic Instability; Geometry; Glycocalyx; Goals; Heritability; Human; Immunodeficient Mouse; In Vitro; Individual; Liquid substance; Localized Malignant Neoplasm; Malignant Neoplasms; Mechanical Stress; Mechanics; Mesenchymal; Mesenchymal Cell Neoplasm; Methods; Microcirculation; Microfluidic Microchips; Microfluidics; Modeling; Molecular Abnormality; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nuclear; Nuclear Envelope; Organ; Patients; Phenotype; Play; Primary Neoplasm; Proliferating; Property; Prostate; Resolution; Role; Rupture; Specimen; Stress; Structure; Testing; Tissue Engineering; Travel; Tumor Cell Biology; biophysical properties; cancer cell; combat; constriction; experience; inhibitor/antagonist; malignant breast neoplasm; micronucleus; migration; molecular imaging; mouse model; neoplastic cell; next generation; programs; repaired; response; tumor; tumor progression; viscoelasticity

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.

抽象的 循环肿瘤细胞从原发性肿瘤传播到远处器官时驱动转移 循环。循环肿瘤细胞的多细胞簇虽然在血液中观察到的频率较低，但 比单个循环肿瘤细胞建立转移的可能性更大，并且存在肿瘤 血液中的簇与患者的预后较差有关。虽然有 许多怀疑对其更大的转移潜力的解释，关于 簇的行为，尤其是在身体狭窄的血管中。最近的证据表明 通过狭窄限制过渡的聚类经历了对结构和组织的动态变化。 微循环中的力导致簇可逆地重组为单文件链以实现 通过狭窄的毛细管船只和核信封的过境破裂并快速修复 在迁移事件中，通过狭窄的收缩。簇中的两个生物物理参数， 细胞粘附强度和核力学对于这些行为至关重要。因为重要 这些参数在转移性进展的许多方面起着的作用，我们假设这些 参数调节簇对微循环中物理力的生物物理响应，并调节 这些相互作用在群体中具有优势的竞争优势中起着重要作用 单个癌细胞用于播种转移。为此，我们提出了三个具体目标。在AIM 1中，我们 将使用内皮的圆网网络开发人类微循环的下一代模型 细胞涂层的微流体设备和几何形状匹配计算模拟。在AIM 2中，我们将 探索细胞间粘附如何影响生物物理反应和形成转移的能力 微循环中的均质与异质簇通过我们开发的 型号。最后，在AIM 3中，我们将研究核包膜破裂，DNA破坏的物理基础， 遗传不稳定性和其他DNA水平会影响与转移性进展有关的影响。理解 微循环中簇的生物物理学与生物学之间的相互作用将阐明 可用于打击簇引起的转移的进展的机制。