A morphogenic cascade emerges from the co-evolution of spheroid fluidization and fracturing of multicellular barriers

Abstract

Cell collectives can undergo solid to fluid states transition and break apart during development and disease. How these processes coordinate collective cell invasion of a tissue barrier, as well as the underlying biological and physical principles, remains unclear. Using a three-dimensional model system of cancer spheroids invading the mesothelium, we find that the mesothelial cell-cell contacts undergo tensile fracturing as the spheroid invades. This tensile fracture is triggered by mesothelial cell apical constriction, a consequence of intercellular integrin complex engagement between the spheroid leader cell and the mesothelial cell. Concurrently, persistent directed migration of spheroid cells propagate the mesothelial fracture. In response, the deformed mesothelium exerts resisting forces on the fluidizing spheroid, leading to a crowding effect and contact inhibition of the fluidizing spheroid. We have uncovered a morphogenic cascade, revealing that the invasion of cells into adjacent cellular and extracellular matrix-rich microenvironment emerges from the co-evolution of spheroid fluidization and mesothelium fracture triggered by intercellular integrin complex engagement.