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

Abstract

AbstractCell collectives migrate and undergo morphological transitions during development and diseases. How cells collectively invade a tissue barrier and its immediate consequence remains elusive. An outstanding challenge is to achieve a comprehensive understanding of the invasion cascade by integrating and applying principles from material science, biophysics, and cell biology. Using a three-dimensional model system of cancer spheroids invading the mesothelium, we show that collective cell invasion emerges from an interplay between spheroid fluidization and fracturing of the multicellular barrier. We found that mesothelial cell- cell contacts undergo tensile fracturing due to spheroid invasion. At the subcellular level, force transmission via intercellular integrin complexes between spheroid and mesothelial cells induces mesothelial cell apical constriction that leads to fracturing. Concurrently, fluidization and directed spheroid cells motility expand the mesothelial fracture. In response, the deformed mesothelium retards spheroid spreading, leading to spheroid cells crowding with contact inhibition of locomotion and proliferation. Our results demonstrate that collective invasion is a morphogenic cascade, revealing that the multicellular barrier undergoing invasion-induced fracture can subsequently force the invaded cells into a dormant state of reduced proliferative potential. Thus, our conclusion may help explain why cancer cells that have invaded a foreign microenvironment tend to enter dormancy.