Resolving cadherin-mediated inter-cell contractile tension in multicellular migration.

Abstract

Cell migration plays an important role in physiological processes of multicellular organisms and cancer metastasis. The change from coherent collective cell motion to individual incoherent motion is a key aspect of metastasis. This motivates this study of how stresses are generated, transmitted and coordinated during collective migration of cancer cells. We focus on the role of cadherins located at adherens junctions, transmembrane proteins that mediate cell-cell adhesion and harness the contractile force of the cell via the acto-myosin cytoskeleton. Cadherins are mechanosensitive and mechanoconductive, and are believed to play an important role in cell coordination during migration by enabling cells to collectively polarize and migrate along the axis of minimal intercellular shear stress. How such collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, as mechanical stresses exerted at adherens junctions have not been accessible experimentally. To determine the impact of cadherins on carcinoma cell contractility, we used Traction Force Microscopy (TFM) and Bayesian Inversion Stress Microscopy (BISM) within fluorescently tagged cadherins clusters. GNE495 was used to modulate these cadherin-based adhesions. This showed an increase in the magnitudes and durations of traction forces, strain energy and shear stresses. A tracking algorithm was used to study the role of cadherins and contractility on cell migration, as we would expect higher contractility to correlate with higher displacements. Instead, cell movement tracked by their Mean Squared Displacement (MSD) decreased after cadherin disruption. This increase in contractile work but decrease in migration suggests that cadherin adhesion dynamics may be crucial in coordinating forces during migration, and loss of this coordination decreases the efficiency of collective migration. This provides valuable insight on tying the biophysics of cadherins to the biology of metastasis and a broader understanding of how intercellular stresses govern multicellular migration.