Collaborative Research: Multiscale and Multiphasic Modeling of Single and Collective Migration in Fibrous Extracellular Matrices

生物细胞感知并响应物理力量，这可以塑造和指导它们的行为。细胞还可以主动产生力，探测周围环境中的材料并使其变形。细胞簇与其环境之间的这些动态相互作用对于包括早期发育和癌症进展在内的广泛活动至关重要。近年来，人们越来越有兴趣揭示是什么驱使细胞从不断增长的集群中逃逸，无论是独立的还是集体的。然而，缺乏对支配这种活动的生物物理学的透彻理解。为了解决这些问题，将开发一种新的计算和实验框架来研究细胞力，粘附和环境物理学之间的相互作用如何驱动细胞增殖，逃逸和侵入身体的远端区域。提出的新工具将影响生物学的许多领域，包括正常和异常组织发育，伤口愈合和组织再生。这些创新的数学模型和方法将推动生物学以及生物工程和生物技术等其他科学领域的计算。目前的数学模型无法预测为什么细胞从增殖集群侵入并独立或集体迁移，这决定了癌症进展期间入侵细胞的转移风险。这个问题将通过一个新的多尺度框架来解决，该框架集成了高度非线性矩阵力学、力介导的细胞信号传导和活性细胞收缩性的计算模型。这种方法将为基质特性促进或阻止细胞入侵的机制提供新的理解，以及为什么细胞倾向于集体移动或单独行动。特别是，细胞介导的基质重塑，长距离力传递和上皮间质转化（EMT）的关键作用将被揭示。细胞侵袭的动力学需要突起的形成、粘连的组装和溶解以及收缩性肌动球蛋白纤维的重塑。这些随机过程将使用动力学蒙特卡罗方法建模，这将明确说明细胞对其环境的响应波动。此外，将开发一种新的组织生长的多尺度生物-化学-力学模型，以预测任意形状的细胞簇的形成，并量化细胞的复杂模式如何从这些簇中出现。这项研究将导致细胞入侵的数学建模的范式转变，明确包括信号，非线性矩阵力学和细胞与矩阵之间的双向递归对话。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Biological cells sense and respond to physical forces, which can shape and guide their behavior. Cells can also actively generate forces, to probe and deform materials in their surrounding environment. These dynamic interactions between clusters of cells and their environment are critical to an immense range of activities including early development and cancer progression. In recent years there has been a growing interest to uncover what drives cells to escape from growing clusters, either independently or in collective streams. However, a thorough understanding of the biophysics governing such activity is lacking. To address these issues, a novel computational and experimental framework will be developed to investigate how the interplay between cellular forces, adhesion, and environmental physics drive cells to proliferate, escape, and invade distant regions of the body. The new tools proposed will impact many areas in biology, including normal and abnormal tissue development, wound healing, and tissue regeneration. The innovative mathematical models and methods will advance computing in biology as well as other fields of science such as bioengineering and biotechnology.Current mathematical models cannot predict why cells invade from a proliferative cluster and migrate either independently or as collective strands, which determines the metastatic risk of invading cells during cancer progression. This problem will be addressed through a novel multi-scale framework that integrates computational models of highly non- linear matrix mechanics, force-mediated cell signaling, and active cell contractility. Such an approach will provide a new understanding of the mechanisms by which matrix properties promote or discourage cell invasion, and why cells tend to either move collectively or act alone. In particular, the critical role of cell-mediated matrix remodeling, long range force transmission, and epithelial-to-mesenchymal transitions (EMT) will be uncovered. The kinetics of cell invasion requires the formation of protrusions, assembly and dissolution of adhesions, and remodeling of contractile actomyosin fibers. These stochastic processes will be modelled using Kinetic Monte Carlo methods, that will explicitly account for fluctuations in the cell’s response to its environment. Additionally, a novel multi-scale bio-chemo-mechanical model of tissue growth will be developed to predict formation of arbitrarily shaped cell clusters and to quantify how complex patterns of cells emerge from such clusters. This research will lead to a paradigm shift in the mathematical modelling of cell invasion by explicitly including signalling, non-linear matrix mechanics and the two-way recursive dialog between cells and the matrix.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.