During development and disease, epithelial cells can migrate collectively, with or without undergoing epithelial- mesenchymal transition (EMT), through heterogeneous matrices, enabling fundamental processes such as branching morphogenesis, fibrosis, and tumor invasion. We have shown that extracellular matrix (ECM) properties beyond the current ECM stiffness, such as confinement and past ECM stiffness, can fundamentally alter epithelial responses. Through a collection of projects, combining experiments and simulations, this proposal will reveal new modes collective cell behaviors in matrices of heterogeneous stiffness and topography. We will measure EMT and migration of epithelial cells around defects in a basement membrane (BM)-like matrix, determine 3D invasion due to defect-induced EMT, build a computational model to understand rate-dependent EMT evolution, and pharmacologically disrupt BM degradation. We will also assess whether the epithelial cells can sense deeply into their matrix and alter responses based on distant stiffening of the matrix. In another project, we will investigate how cell sheets migrate in 3D-like confined environments of tunable stiffness and topography. We will connect nuclear shape with cytoskeletal reorganization to understand how cells adapt to distinct stiffnesses of past and present matrices. Outcomes of these projects will enable new fundamental understanding of epithelial cell responses to matrix heterogeneities that have remained unexplored and could reveal novel targets for diseases such as fibrosis and cancer.

Public Health Relevance

The proposed research will reveal new modes of epithelial cell responses to various mechanical heterogeneities present in their microenvironments. Novel findings from this work may help devise new therapeutic strategies by blocking dysfunctional EMT and collective migration of epithelial cells due to physical defects, discontinuities and confinements of the surrounding tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM128764-02
Application #
9748598
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Xu, Jianhua
Project Start
2018-08-01
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mathur, Jairaj; Sarker, Bapi; Pathak, Amit (2018) Predicting Collective Migration of Cell Populations Defined by Varying Repolarization Dynamics. Biophys J 115:2474-2485