The physics of cell migration in confining matrices

Cell migration plays a central role in cancer progression. For example, in breast cancer, breast cancer cells will collectively invade through the basement membrane and into the surrounding collagen-rich stromal matrix in a critical step towards metastasis. Complementarily, infiltration of immune cells, such as monocytes or T cells, into the tumor microenvironment can also play an important role in regulating progression. The stromal matrix in the breast tumor microenvironment is marked by a dense and fibrillar ECM and striking changes in matrix architecture, stiffness, viscoelasticity, and plasticity. In these confining matrices, a key question emerges as to how these cells are able to generate migration paths. Here, we examine how change in matrix mechanical properties regulate the processes of collective breast cancer cell and immune cell migration and elucidate the underlying mechanisms of migration path generation.

We study collective breast cancer cell migration, monocyte migration, and T cell migration in interpenetrating networks of alginate and collagen with tunable mechanical properties that are nanoporous or confining. The collagen fibers model the collagen observed in the breast tumor stromal matrix while the alginate provides an inert scaffolding with which to tune the mechanical properties of the matrix. Underlying mechanisms are uncovered using a combination of time-lapse microscopy, traction strain microscopy, and perturbation studies.

Our work reveals new regulators and mechanisms of cell migration. Increasing plasticity to breast cancer relevant ranges facilitates invasion of breast cancer cells, with increasing stiffness potentiating a transition from single cell to collective invasion. Mechanistically, the swirling motion of breast cancer cells radially aligns collagen fibers, due to negative normal stress in collagen-rich matrices, to enable collective invasion. Enhanced stiffness and viscoelasticity promote monocyte migration, with monocytes using pushing forces at the leading edge mediated by actin polymerization to generate migration paths. Finally, we find that matrix shear strength regulates T cell migration. Together, these results shed new insights into the diverse mechanisms of migration cells employ to migrate in confining extracellular matrices relevant to the tumor microenvironment.