Reciprocal intra- and extra-cellular polarity enables deep mechanosensing through layered matrices

Adherent cells migrate on layered tissue interfaces to drive morphogenesis, wound healing, and tumor invasion. Although stiffer surfaces are known to enhance cell migration, it remains unclear whether cells sense basal stiff environments buried under softer, fibrous matrix. Using layered collagen-polyacrylamide gel systems, we unveil a migration phenotype driven by cell-matrix polarity. Here, cancer (but not normal) cells with stiff base matrix generate stable protrusions, faster migration, and greater collagen deformation because of “depth mechanosensing” through the top collagen layer. Cancer cell protrusions with front-rear polarity produce polarized collagen stiffening and deformations. Disruption of either extracellular or intracellular polarity via collagen crosslinking, laser ablation, or Arp2/3 inhibition independently abrogates depth-mechanosensitive migration of cancer cells. Our experimental findings, validated by lattice-based energy minimization modeling, present a cell migration mechanism whereby polarized cellular protrusions and contractility are reciprocated by mechanical extracellular polarity, culminating in a cell-type-dependent ability to mechanosense through matrix layers. [Display omitted] •Cells (cancer but not normal) mechanosense deep through collagen layers•Polarized protrusions and cellular forces perform polarized collagen remodeling•Matrix polarity couples with cell polarity to generate long-distance force propagation•Collagen crosslinking or Arp2/3 inhibition disables matrix polarity and depth sensing Walter et al. show that cancer (but not normal) cells with strong front-rear polarization migrate faster and mechanosense deep through collagen layers with stiff basal matrix. This depth mechanosensing requires cooperation between cell and matrix polarities generated by polarized cellular forces. Collagen crosslinking or Arp2/3 inhibition disable depth-sensitive cell migration.