(16f) Dynamic Tensile Forces Drive Collective Migration through Three-Dimensional Extracellular Matrices

Authors: 
Piotrowski, A., Princeton University
Siedlik, M. J., Princeton University
Nelson, C. M., Princeton University
Gjorevski, N., Princeton University

Introduction: Collective migration drives a variety of dynamic biological and developmental processes, including wound healing, angiogenesis, branching morphogenesis, and cancer invasion. These processes are fundamentally physical, though our understanding of the physical mechanisms by which groups of cells move cohesively through dense three-dimensional extracellular matrices remains incomplete. For this reason, this work sought to investigate the means by which mechanical interactions between a migrating cohort and the surrounding extracellular matrix (ECM) regulates collective migration.

Approach: We used arrays of microfabricated tissues to elucidate the physical mechanisms by which multicellular cohorts move through a three-dimensional (3D) ECM. Cells underwent collective invasion predictably from specific locations within the microfabricated tissues, allowing for high-throughput analysis with high statistical confidence. Matrix deformations and the corresponding mechanical forces which accompanied migration were evaluated by tracking the movements of fluorescent beads embedded in the surrounding ECM.

Results and Discussion: Using 3D traction force microscopy, we found that cells exert tensile forces on the surrounding ECM while undergoing collective migration. These forces both propelled cells forward and stimulated mechanotransduction signaling at the leading edge of the migrating cohort. Confocal reflectance microscopy revealed that the matrix ahead of the migrating cohort was remodeled into highly aligned fiber bundles along which the cohort preferentially migrated. Moreover, timelapse imaging showed that cohort extension was highly dynamic, and that variations in cohort length were highly correlated and in phase with deformations and tensile forces in the ECM. These results suggest both mechanical and signaling roles for dynamic tensile forces during collective migration.