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: 10152522
• 负责人: Daniel A. Haber
• 金额: $ 53.46万
• 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/10152522
• 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; 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 当循环肿瘤细胞从原发肿瘤通过 循环。循环肿瘤细胞的多细胞簇虽然在血液中很少观察到，但 比单个循环肿瘤细胞和肿瘤的存在更有可能建立转移 血液中的簇与患者的预后较差有关。虽然有 对于它们更大的转移潜力有许多可疑的解释，但关于 簇的行为，尤其是在身体的狭窄血管中。最近的证据表明 穿过狭窄限制的集群会经历结构和组织的动态变化。 微循环中的力量导致簇可逆地重新组织成单文件链，从而使 通过狭窄的毛细血管大小的血管，核膜破裂并迅速修复 在通过狭窄狭窄的迁徙活动期间。簇内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。因为重要的 这些参数在转移进展的许多方面发挥着作用，我们假设这些参数 参数调节簇对微循环中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，我们提出三个具体目标。在目标 1 中，我们 将开发具有圆形内皮细胞网络的下一代人体微循环模型 细胞涂层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 通过使用我们开发的微循环中的同质簇与异质簇 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 水平影响与转移进展有关。理解 微循环内簇的生物物理学和生物学之间的相互作用将阐明 可用于对抗簇引发的转移进展的机制。