Effects of migrating cell-induced matrix reorganization on 3D cancer cell migration

The migration of cells is fundamental to a number of physiological/pathological processes, ranging from embryonic development, tissue regeneration to cancer metastasis. Current research on cell migration is largely based on simplified in vitro models that assume a homogeneous microenvironment and overlook the modification of extracellular matrix (ECM) by the cells. To address this shortcoming, we developed a nested three-dimensional (3D) collagen hydrogel model mimicking the connective tissue confronted by highly malignant breast cancer cells, MDA-MB-231. Strikingly, our findings revealed two distinct cell migration patterns: a rapid and directionally persistent collective migration of the leader cells and a more randomized migration in the regions that have previously been significantly modified by cells. The cell-induced modifications, which typically include clustering and alignment of fibers, effectively segmented the matrix into smaller sub-regions. Our results suggest that in an elastic 3D matrix, the presence of adjacent cells that have modified the matrix may in fact become physical hurdle to a migrating cell. Furthermore, our study emphasizes the need for a micromechanical understanding in the context of cancer invasion that allows for cell-induced modification of ECM and a heterogeneous cell migration.