Cadherin dynamics and cortical tension in remodeling cell-cell adhesion during EMT.

Epithelial-to-mesenchymal transition (EMT), a key process in cancer metastasis and fibrosis, disrupts cellular adhesion by replacing epithelial E-cadherin with mesenchymal N-cadherin. While, how the shift from E-cadherin to N-cadherin impacts molecular-scale adhesion mechanics and cluster dynamics-and how these changes weaken adhesion under varying mechanical and environmental conditions-remains poorly understood, limiting our ability to target EMT-driven pathological adhesion dynamics. Here, we developed a unified lattice-clutch model to investigate cadherin clustering, cortical tension, and adhesion strength during EMT. Using atomic force microscopy experiments, we measured the mechanical properties of single cadherin trans-bonds and cadherin-mediated cell-cell and cell-matrix adhesions across varying conditions. Our results demonstrate that N-cadherin trans-bonds are mechanically weaker than E-cadherin trans-bonds, leading to reduced adhesion strength during EMT. Computational modeling and experimental validation further revealed that EMT impairs cadherin clustering and cortical tension regulation, which collectively weaken both cell-cell and cell-matrix adhesions, particularly on stiff substrates. These findings highlight how EMT disrupts adhesion strength at multiple scales-from individual cadherin bonds to collective cluster dynamics. Our study elucidates how EMT-driven changes in cadherin type weaken adhesion strength and mechanotransduction, providing insights into cellular adhesion mechanics and potential therapeutic strategies for targeting EMT-associated diseases such as cancer metastasis and tissue remodeling.