Abstract

Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. We use transparent zebrafish epidermis to model simple epithelia to directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death—cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Mechanics not only drive dedifferentiation but also stromal cell differentiation, as cells migrate through tight confinement. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses.