Epithelial density controls cell migration through an adhesion-nucleus mechanotransduction pathway

Cell density is thought to regulate tissue growth, homeostasis, and regeneration, yet how cells sense and respond to density remains poorly understood. To investigate density-dependent mechanotransduction, we combined genetically encoded biosensors with quantitative fluorescence microscopy in epithelial cells subjected to genetic, pharmacological, and mechanical perturbations. We found that low epithelial density promotes focal adhesion growth, causing mechanical relaxation of vinculin and release of its competitive binding with FAK and ERK. This enables FAK to bind and activate ERK in the cytoplasm. Cytoskeletal tension transmitted through LINC complexes drives their nuclear translocation, where low density induces ERK-dependent chromatin decondensation and increased nuclear envelope tension. This recruits and activates cPLA2, leading to arachidonic acid production and enhanced cell migration. Together, these findings identify a mechanochemical pathway linking cell density to epithelial migration via ERK, cPLA2, and mechanically regulated signaling from adhesions to the nucleus. Significance statement In multicellular organisms, cells constantly experience crowding, yet how they detect changes in cell density and convert them into biological responses is not well understood. Here, we show how low cell density mechanically triggers signaling inside epithelial cells to promote migration. When cells are sparse, adhesion sites grow and release key signaling proteins that move into the nucleus stretched by the cytoskeleton. These mechanical and biochemical inputs alter nuclear structure, activates lipid signaling, and boosts cell migration. By revealing how mechanical forces, cell adhesions, and nuclear signaling work together, this study provides a clear mechanistic link between cell density and migration, a process central to tissue growth, repair, and disease progression.