Dynamics of single cell-cell junctions as an indicator of cell state switch

Abstract Cell-cell junctions (CCJs) are dynamic biopolymeric systems essential for adherence of biological cells organizing into a tissue or organ. In vertebrate organisms, CCJs present in stable epithelial tissues are maintained primarily by cell-to-cell protein bridges made of an adhesion receptor E-cadherin. CCJs are destabilized during Epithelial (E) to mesenchymal (M) transformation (EMT), an essential step in cancer metastasis, where cells switch states and acquire migratory features. An essential trigger for EMT is a cadherin switch process from E-cadherins with N-cadherin, another cadherin isoform. EMT proceeds through several intermediate states referred to as hybrid E/M cells. These states are characterized by mixed levels of E- and N-cadherins at the junctions and exhibit versatile cancerous traits that are more aggressive than cancerous fully mesenchymal cells. As a result, many such states have emerged as key targets in cancer therapy. However, development of a therapeutic design to counter the hybrid E/M cells has been limited by the absence of a comprehensive understanding of the mechanics and dynamics of hybrid E/M states. Here, we develop a physical model of CCJs as a non-equilibrium system composed of a variable ratio of E- and N-cadherins, considered as coarse-grained molecules driven by ATP-powered machinery observed at CCJs. Our model predicts a robust measure of strength of junctions that captures previous experimental observations, and reveals a minimal mechanochemical landscape of hybrid E/M states. We show the emergence of several groups of CCJ states in this landscape with variable adhesion strengths, many of which resemble different hybrid E/M-characteristics observed experimentally. Finally, we identify that a difference in mechanosenstivity of the two cadherin isoforms towards cytoskeletal forces could be why the hybrid E/M states come into existence. Competing Interest Statement The authors have declared no competing interest.