Nuclear mechanics controls the temporal dynamics of cell unjamming

Abstract

Cell unjamming in dense tissues is a complex but essential process in embryogenesis and cancer metastasis. Increasing evidence suggests that nuclear mechanics and density effects play a vital role in collective cell unjamming. However, state-of-the-art cell-shape-based theories fail to include nuclear and density effects, while computer models featuring rigid nuclei disagree with experimental observations of elongated nuclei promoting unjamming. Here, we introduce a computational model of confluent cells with explicitly deformable nuclei to study the dynamics of cell unjamming. Our simulations show an unjamming transition controlled by nuclear size and shape, reconciling conflicting theories of density-driven versus shape-driven mechanisms. We predict general relations connecting cellular and nuclear shape to collective cell motion, verified experimentally in distinct monolayers of MCF-10A and MDA-MB-436 breast cells, with striking accuracy. Our work establishes a rational connection between nuclear mechanics and tissue-scale rigidity transitions, highlighting the nucleus's key role in collective cell unjamming.