Substrate heterogeneity promotes cancer cell dissemination through interface roughening.

Although studies of tumor invasion have mainly emphasized the evolution of genetic and epigenetic heterogeneity, cellular behaviors also depend on the physical microenvironment. Yet, the tumor microenvironment is both complex and continuously remodeled, making it hard to rigorously test its causal influence on tumor dissemination. Here, we adopted a reductionist approach to studying tumor cell invasion in microengineered environments of tunable patterned geometries. We find that not only the presence of obstacles but more unexpectedly their spatial disorder causes a drastic shift from a collective to a single-cell mode of invasion-comparable in strength to loss of cell-cell adhesion. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell dissemination results both from local geometrical constraints and a global integration of spatial disorder over time. We identify generic universality classes of invasion dynamics dependent on environmental geometry, enabling us to identify quantitative physical principles for tumor dissemination.