Before revision:  Analytical calculations revealed that the monolayer integrity of cell sheet is lost to delamination by a spontaneous symmetry breaking, inherently depending on the 3D foam geometry of cells; i. e., the instability spontaneously appears when the cell density in the sheet plane increases and/or when the number of neighboring cellsdecreases, as observed in vivo.
After revision:  Analytical calculations revealed that the monolayer integrity of cell sheet is lost to delamination by a spontaneous symmetry breaking, inherently depending on the 3D foam geometry . We found that when the cells composing the monolayer have homogeneous mechanical properties, cells are extruded from the monolayer when the symmetry of the 3D geometry is broken due to an increase in cell density or a decrease in the number of topological neighbors around single cells. Those results suggest that mechanical instability inherent in the 3D foam geometry of epithelial monolayers is sufficient to drive epithelial cell extrusion. In the situation where cells in the monolayer actively generate contractile or adhesive forces under the control of intrinsic genetic programs, the instability spontaneously appears when the cell density in the sheet plane increases and/or when the number of neighboring cellsdecreases, as observed in vivo.