It is becoming clear that collective cell migration is involved in the dissemination of tumor cells. In collective cell migration, cells move through migration of cohesive multi-cellular units, the specifics of their motility depend on numerous factors including cell-cell, cell-matrix interaction, adhesion strength, extracellular matrix rigidty, organization of the cellular cytoskeleton etc. How each individual factor affect the collective cel migration is still poorly understood and needs further investigation. This project will investigate fundamental mechanisms of collective cell migration from cell molecular biology perspective as well as from mechanics viewpoint. The research objective of this proposal is to establish a multiscale approach to investigate cell-cell, cell-matrix interaction and their influences on collective cell migration. The central hypothesis of the proposed research is that collective cell migration depends on interactions between cells and their microenvironment which can be quantified by biomechanical and biophysical parameters in an integrated multiscale model. To test the hypothesis, computational modeling and simulation approaches will be developed and three specific aims will be addressed:
Aim 1 To build an active cell model with internal structures to capture the essential features of cell membrane, cytoskeleton and cell nucleus:
In Aim 1, we propose to use liquid crystal and liquid crystal elastomers to model major cell components.
Aim 2 To develop a mutliscale cell migration model and to elucidate how different factors control collective cell migration motions:
In Aim 2, we propose to use coarse-grained potential forces to model the cell-cell/matrix interaction. After the model validation, we will systematically study how cell-cell/matrix interaction, adhesion strength, extracellular matrix rigidity, organization of the cellular cytoskeleton will affect collective cell migrations motions.
Aim 3 To develop advanced simulation techniques for cell mechanics simulations:
In Aim 3, a total Lagrangian meshfree formulation will be developed and a related Galerkin weak formulation will be derived for numerical computation. The main advantage of adopting a meshfree Lagrangian formulation is its ability to avoid remeshing and easy-tracking of cell surface and interface. It i anticipated that the multiscale model can capture the essential features of collective cell migration. As a result, it will significantly enrich our knowledge in some fundamental theories in cell mechanics and it will provide a theoretical underpinning for study of cell-cell interaction an tumor metastasis mechanisms.
Cell migration plays an essential role in many biological and physiological processes including morphogenesis, wound healing and tumor metastases. Metastases are responsible for as much as 90% of cancer-associated mortality, yet it is one of the least understood mechanisms in cancer pathogenesis. To investigate the mechanisms underlying collective cell migration is far overdue for the outcome could lead to novel therapeutic strategies and applications for controlling invasive tumor cells.
|Lin, Liqiang; Zeng, Xiaowei (2017) Computational study of cell adhesion and rolling in flow channel by meshfree method. Comput Methods Biomech Biomed Engin 20:832-841|