Active Mechanics Governs Three-Dimensional Cell-in-Cell Formation

The formation of cell-in-cell structures is a complex dynamic process that profoundly influences tissue development and cancer progression. Here, we decipher the physical principles governing three-dimensional (3D) cell-in-cell formation, including cannibalism and entosis, and their cooperation that are observed experimentally. We show that active engulfing cells behave like a material flow or deform as a solid, determined by the cytoskeleton arrangement, whereas the cytoskeleton in invading cells can spontaneously break the left-right symmetry, organizing into a 3D vortex-like topological defect to facilitate internalization. The microscopic stiffness mismatch between the interacting cells markedly affects the cell-in-cell formation and may even lead to escape of the internalized cells. Backed by prior experiments, we predict that the stress localization at the interacting interface may induce the formation of a contractile multimolecular ring structure, favoring cell penetration and cavity closure. Our findings provide a multiscale physical basis for understanding cell-in-cell dynamics in various physiological and pathological contexts.