A Computational Study of Cell Locomotion in Complex Environments: Towards a Fluid Mechanical Understanding of Cancer Progression

癌症仍然是美国第二大死亡原因。超过90%的癌症相关死亡是由于疾病进展到远离原发肿瘤的继发部位，这一过程被称为转移。为了转移，癌细胞首先从原发肿瘤中分离出来，通过周围组织迁移到附近的血液或淋巴管。癌细胞通过周围组织的迁移是癌症进展的关键步骤，也是本研究的重点。一种特殊的迁移模式被称为变形虫迁移，其中单个癌细胞利用称为假足的细胞体的手指状突起挤压周围组织。变形虫迁移是最具侵袭性的癌症进展机制，据报道其迁移速度最快。此外，转移细胞可以转化为变形虫运动，以避免某些化疗。周围的组织，类似于多孔介质，创造了一个复杂的、三维的、拥挤的环境，细胞可以在其中导航。众所周知，细胞的灵活性和周围组织的机械特性决定了迁移特性。然而，由于其复杂性，变形虫迁移的机制尚不清楚。本提案的研究目的是提供基于流体力学的变形虫通过组织迁移的理解。该项目还将包括高中生的外展计划和本科生的研究经验。该项目的主要目标是进行高保真计算建模研究，以了解细胞流变学和组织几何形状对变形虫运动的同时作用。建模包括通过假足的生长和收缩动态改变细胞形状来解决细胞的极端可变形性，使用动态模式形成模型来解决粗粒蛋白反应，将细胞膜变形与细胞质和细胞外液耦合，并解决周围组织的微观结构细节。用浸入边界法耦合细胞膜变形、组织微观结构、流体流动和蛋白质反应扩散。模拟将通过改变细胞流变学和组织微观结构（例如孔隙率和孔隙形状）来进行，以了解它们如何影响整体迁移动力学。同时，将考虑在人工支架中进行细胞运动实验来验证模型。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cancer remains the second highest cause of mortality in the US. More than 90% of cancer-related deaths are due to progression of the disease to secondary location(s) away from the primary tumor, a process known as metastasis. In order to metastasize, cancer cells first detach from the primary tumor and migrate through the surrounding tissue to reach to a nearby blood or lymphatic vessel. Migration of cancer cells through the surrounding tissue is a critical step in cancer progression, and is the focus of this study. One specific mode of migration is termed as amoeboid migration, in which individual cancer cell squeezes through the surrounding tissue by using finger-like protrusions of the cell body known as pseudopods. Amoeboid migration is the most aggressive mechanism of cancer progression with reportedly the highest migration speed. Additionally, metastatic cells can convert to amoeboid motility to avoid certain chemotherapy treatments. The surrounding tissue, resembling a porous medium, creates a complex, three-dimensional and crowded environment through which the cells navigate. It has been known that flexibility of the cells, and the mechanical properties of surrounding tissue determine the migration characteristics. However, because of its complexity, the mechanisms underlying amoeboid migration are poorly understood. The research objective of this proposal is to provide a fluid mechanics-based understanding of amoeboid migration through tissue. The project will also include outreach program for high-school students and research experience for undergraduate students.The primary goal of this project is to conduct a high-fidelity computational modeling study to understand the simultaneous roles of cell rheology and tissue geometry on amoeboid motility. The modeling involves resolving extreme deformability of the cells with dynamically changing cell shapes due to growing and retracting pseudopods, coarse-graining protein reactions using a dynamic pattern formation model, coupling the cell membrane deformation with cytoplasmic and extracellular fluid, and resolving microstructural details of the surrounding tissue. An immersed-boundary method is used coupling cell membrane deformation, tissue microstructures, fluid flow, and protein reaction-diffusion. Simulations will be performed by varying the cell rheology and tissue microstructure (for example, porosity and pore shape) to understand how they affect overall migration dynamics. In parallel, cell motility experiments in artificial scaffolds will be considered to validate the 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.