Rigidity sensing regulates epithelial monolayer integrity

Loss of epithelial integrity is known to play a pathological role in cancer metastasis while serving a physiological role in several developmental processes. Yet the physical mechanisms leading to hole formations within epithelial monolayers remains to clarified. Here, we observed the spontaneous formation of holes within epithelial monolayers in a substrate rigidity dependent manner which predominantly occurred on soft substrates. To decipher the physical mechanism of hole opening both at the cell and tissue levels, we design a cell-based computational framework (called vertex model) whereby we evaluate two possible models where holes may either form along junctions experiencing high tensile normal stresses (model 1) or along junctions of fast shear strain (model 2). We find that model 1 is more successful to describe the experimental observations on the location of hole opening events. In addition, based on a continuum hydrodynamic theory of 2D epithelial tissues (called active nematic theory), we propose that the forces driving the hole formation may be non-conservative (i.e. strain-rate related) with an overall dynamics displaying an effective inertia related to an expectedly long cell-shape relaxation time (in the 100 min range).