Computational Modeling for Predicting 3D Cancer Cell Invasion into the Extracellular Fiber Network

细胞与周围组织的物理相互作用在癌症转移、伤口愈合、发育、血管生成等许多正常和疾病情况下都是非常重要的。我们仍然只对真实组织的这一点有一个很小的定量了解。一种还不能定量理解的相互作用是，细胞延伸出被称为“丝状足”的薄结构，这种结构可以感知化学物质，并“感觉”组织周围部分的僵硬。这项研究将从最精细的尺度创建丝足的三维(3D)模型，通过中间尺度模拟细胞周围胶原纤维的3D网络中的分子，其中粘弹性网状结构的分子因丝足对网络的推动和拉动而经历大的变形，并且在最大尺度上，将细胞的迁移模拟为多个丝足、改变周围网格的分子的分泌和细胞的拉力的协调活动。这项研究将有助于将计算细胞力学带入主流，为研究人员、教育工作者和学生建立一个三维细胞迁移模拟软件。这些工具将以网络教程模块和开放软件的形式提供给世界各地的教育工作者、学生和研究人员。该项目还将形成一个软件用户和研究合作者的论坛。这项研究项目将进一步推动美国了解有助于公民健康和疾病的细胞活动的目标。该项目的计算模型将显著促进对3D细胞侵入ECM纤维网络的定量理解。它将包括结合动力学水平上的细胞-细胞外基质相互作用，并将众多关键机制整合到整个细胞水平的迁移建模中。将进行体外微流控实验，以确定未知参数并验证计算模型。所得到的模型将被用来预测3D ECM中的细胞迁移如何受到硬度以及ECM孔隙率、单纤维直径和交联剂性质的影响。它将被用来预测3D细胞侵袭ECM是否存在一个最佳的分泌水平；过多的分泌使ECM纤维网络迅速退化并使其变得过于柔软，而过少的分泌则阻碍细胞侵袭到ECM。一组细胞可以通过ECM中的应力和应变传播相互通信，并作为集体事件创造迁移行为。集体细胞迁移的紧急行为将使用多尺度计算模型进行预测。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Physical interaction of a cell with the surrounding tissue is very important in cancer metastasis, wound healing, development, angiogenesis and many other normal and disease conditions. We still have only a small quantitative understanding of this for real tissues. One type of interaction that is not understood quantitatively is where a cell extends thin structures called a 'filopodia' that sense chemicals and "feel" the stiffness of the surrounding parts of the tissue. This research will create a three dimensional (3D) model of filipodia from the finest scale, to model the molecules in the 3D network of collagen fibers around the cell through the intermediate scale, where the molecules for viscoelastic mesh structures that undergo large deformations caused by the filopodia pushing and pulling on the network, and at the largest scale, model the migration of the cell as a coordinated activity of multiple filopodia, secretions of molecules that change the surrounding mesh and the pulling forces of the cell. This research will help to bring computational cell mechanics into the mainstream by building a 3D cell migration simulation software for researchers, educators, and students. The tools will be available as web tutorial modules and open software for educators, students, and researchers around the world. The project will also form a Forum of software users and research collaborators. This research project will further the goal of the United States to understand the activities of cells that contribute to health and disease of its citizens.This project's computational model will significantly advance the quantitative understanding of 3D cell invasion into the ECM fiber network. It will include cell-ECM interactions at the binding kinetics level and integrate the numerous key mechanisms into the modeling of whole cell-level migration. In vitro microfluidic experiments will be conducted to determine unknown parameters and verify the computational model. The resultant model will be used to predict how cell migration in 3D ECM is influenced by the stiffness and, also, ECM porosity, single fiber diameter, and cross-linker properties. It will be used to predict whether there is an optimal MMP secretion level for 3D cell invasion into ECM; too much secretion of MMP rapidly degrades the ECM fiber network and makes it too soft, while too little secretion of MMP impedes the cell to invade into ECM. A group of cells can communicate with one another through stress and strain propagation in the ECM and create migratory behaviors as a collective event. The emergent behavior of collective cell migration will be predicted using the multi-scale computational model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.