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

描述(由申请人提供)：计算工具在推动生物医学研究进展方面变得越来越重要。这项提议的目的是应用新兴技术发展多尺度计算方法，以研究动态剪切力作用下近壁区异型细胞-细胞的碰撞和粘连。特别是，我们关注的是白细胞(PMN)-黑色素瘤细胞栓子在非线性剪切流中的形成，以及随后由于细胞-细胞聚集而与血管内皮细胞(EC)的捆绑。肿瘤细胞与血管壁的黏附程度受受体-配体键的动态形成/破坏、流体力学剪切环境和循环内异型细胞群的控制。初步研究发现，PMN增加了黑色素瘤细胞的外渗，这涉及PMN最初拴在EC上，然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了一个重要的假设，即PMN促进的黑色素瘤细胞在EC上的停滞是由细胞间黏附分子-1(ICAM-1)/β2-整合素结合介导的，并受流体动力学剪切率和异型细胞群的影响。这项研究的基本原理是使用创新的多尺度计算流体动力学(CFD)和种群平衡(PB)建模来生成计算工具，以研究促进肿瘤细胞与EC黏附和随后的外渗的异型细胞-细胞相互作用。具体目标是：1)建立PB模型，以统计方式模拟剪切诱导的黑色素瘤细胞与EC附近的PMN的碰撞/聚集；2)开发三维CFD模拟，以评估PMN-黑色素瘤细胞相互作用在EC抑制黑色素瘤中的作用；3)通过体外流动实验验证模型，并利用该模型扩展流动条件下肿瘤细胞黏附的分子机制的现有知识。这项研究将为血流动力学、异型细胞群和PMN-黑色素瘤黏附在转移过程中转移癌细胞在微循环中向EC募集的复杂作用提供新的证据，这将对培育新的跨学科癌症治疗方法具有重要意义。

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.