Integrating Four-Dimensional Cell Migration Modeling with Quantitative Experiments

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Many eukaryotic cells are able to move, an ability that plays an important role in a number of biological processes, including embryogenesis, development, wound healing, and pathological diseases, including inflammation and cancer metastasis cancer. This motion occurs in a variety of extracellular environments, including fibrous extracellular matrix (ECM). The biophysical properties of the ECM, including dimension, stiffness, and degree of confinement, can critically affect the migration of cells but the mechanisms are poorly understood. The research team will develop mathematical models that describe cells as 3-dimensional (3D) objects with changing shapes and create techniques that can address cell interactions with fibrous ECM networks. They will create a modeling platform that will be applicable and extendable to a wide range of cell migration problems. They will then integrate their modeling with novel and quantitative experimental data that they will generate. Specifically, their experiments will quantify cell migration in ECM with carefully controlled properties, focusing on the ECM-induced transition between single and collective migration and between unidirectional and rotational collective migration. The project activities will include the training of high school, undergraduates, and graduate students who will be directly involved in the proposed research. The team members will also extend their existing collaboration with two local high school, the Preuss Charter School, a top local high school that accepts students only from disadvantaged families, and Clairemont High School. The goal of this project is to develop mathematical models that are able to describe cells as 3D objects with changing morphologies and create techniques that can address interactions between cells and fibrous ECMs. The research team will focus on the dynamics of cells, resulting in 4D (3D space+1D time) cell migration modeling. The model will be based on the phase-field description which avoids the need to explicitly track and parameterize the deforming cell membrane, which can naturally incorporate intra-cellular signaling pathways, and which can be easily extended to describe collective migration. The experiments will quantify cell migration in ECM with carefully controlled properties, focusing on the ECM-induced transition between single and collective migration and between unidirectional and rotational migration. The experimental results will be incorporated into their models while the modeling will be used to generate experimentally testable predictions. The specific aims for the project are 1) to develop a mathematical model for deformable 3D cells and determine how single vs. collective migration is regulated by ECM properties and 2) to develop a mathematical model for confined migration and determine how unidirectional vs. rotational collective migration is regulated by cell-ECM interactions.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.