Multiscale modeling of leukocyte-tumor cell adhesion to endothelium in shear flow

描述（由申请人提供）：计算工具在生物医学研究中变得越来越重要。本提案的目的是应用新兴技术开发多尺度计算方法，研究动态剪切力下近壁区域的异型细胞-细胞碰撞和粘附。特别是，我们专注于白细胞（PMN）-黑色素瘤细胞栓子形成的非线性剪切流和随后的拴系到血管内皮（EC）作为细胞-细胞聚集的结果。肿瘤细胞粘附于血管壁的程度由受体-配体键的动力学形成/破坏、流体动力学剪切环境和循环内的异型细胞群体控制。初步研究发现，中性粒细胞增加了黑色素瘤细胞外渗，这涉及中性粒细胞最初拴在EC上，随后捕获黑色素瘤细胞并使它们保持在EC附近。结果表明，一个新的发现，并导致一个重要的假设，即中性粒细胞促进黑色素瘤细胞对EC的逮捕是介导的细胞间粘附分子-1（ICAM-1）/β 2-整合素结合，并受到流体动力学剪切速率和异型细胞群体。本研究的基本原理是使用创新的多尺度计算流体动力学（CFD）和群体平衡（PB）建模来生成计算工具，以研究促进肿瘤细胞粘附到EC和随后外渗的异型细胞-细胞相互作用。具体目标是：1）开发PB模型，以统计方式模拟剪切诱导的黑素瘤细胞与EC附近的PMN的碰撞/聚集; 2）开发3-D CFD模拟，以评估PMN-黑素瘤细胞相互作用在EC上的黑素瘤停滞中的作用;第三章通过使用体外流动实验验证模型，并使用模型扩展肿瘤细胞粘附分子机制的现有知识，流动条件这项研究将产生新的证据，血液动力学的复杂作用，异型细胞群，和PMN-黑色素瘤粘附在招聘转移癌细胞转移过程中的微循环EC，这将是重要的，在促进新的跨学科的方法来治疗癌症。

DESCRIPTION (provided by applicant): Computational tools have become increasingly important in enabling progress in biomedical research. The objective of this proposal is to apply emerging technologies in developing multi-scale computational approaches for studying heterotypic cell-cell collision and adhesion in the near wall region under dynamic shear forces. In particular, we focus on leukocyte (PMN)-melanoma cell emboli formation in a non-linear shear flow and subsequent tethering to the vascular endothelium (EC) as a result of cell-cell aggregation. The extent of tumor cell adhesion to a vessel wall is governed by the kinetic formation/disruption of receptor- ligand bonds, the hydrodynamic shear environment and the heterotypic cell populations within the circulation. Preliminary studies found PMNs increased melanoma cell extravasation, which involves PMNs initially tethering on the EC and subsequently capturing melanoma cells and maintaining them in close proximity to the EC. Results have indicated a novel finding and led to an important hypothesis that PMN-facilitated melanoma cell arrest on the EC is mediated by intercellular adhesion molecule-1 (ICAM-1)/beta2-integrin binding and is influenced by hydrodynamic shear rates and heterotypic cell populations. The rationale for this research is to generate computational tools using innovative multi-scale computational fluid dynamics (CFD) and population balance (PB) modeling to study the heterotypic cell-cell interactions that facilitate tumor cell adhesion to the EC and subsequent extravasation. Specific aims are: 1) develop a PB model to simulate the shear-induced collision/aggregation of melanoma cells to PMNs near the EC in a statistical manner; 2) develop a 3-D CFD simulation to assess the role of PMN-melanoma cell interaction in melanoma arrest on the EC; 3) validate the models by using in vitro flow experiments and use the models to expand the current knowledge of the molecular mechanisms of tumor cell adhesion under flow conditions. This study will yield new evidence for the complex role of hemodynamics, heterotypic cell populations, and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC in the microcirculation during metastasis, which will be significant in fostering new cross-disciplinary approaches to cancer treatment.