Reprinted from original article by copyright permission of The Rockefeller University Press

Disruption of cell-cell adhesions is required for epithelial cells to initiate migration and invade other tissues during epithelial-mesenchymal transitions (EMT). Madin-Darby kidney cells loose their cell-cell junctions and scatter upon exposure to hepatocyte growth factor (HGF), mimicking many aspects of EMT. Previous studies have suggested that the extracellular matrix (ECM) can alter cell-cell adhesions during scattering, and de Rooij and colleagues now report in J. Cell Biol. that integrin-mediated cytoskeletal tension provides the signal that breaks apart cell-cell junctions.

Previous studies have focused on the idea that downregulation of E-cadherin at cell-cell adhesions is required for scattering. However, de Rooij and colleagues find that HGF treatment did not reduce E-cadherin at cell-cell junctions, and time-lapse imaging revealed that GFP-E-cadherin disappears only once cells move apart, not before, suggesting that E-cadherin downregulation cannot trigger scattering. Analysis of the actin cytoskeleton provided an important clue for what might be driving cells to scatter: F-actin bundles attached to cell-matrix adhesions appeared to be under increased tension following addition of HGF.

As the ECM is known to influence the actin cytoskeleton and the breakdown of cell-cell junctions, the authors examined the influence of different ECM proteins on scattering efficiency. Indeed, substrates which increase adhesion, such as collagen and fibronectin, promoted HGF-induced cell scattering, while the less adhesive substrate laminin 1 caused slower disruption of cell-cell adhesions. These effects correlated with changes in cytoskeletal organization: cells that scattered more quickly had thicker actin bundles and larger focal adhesions. More importantly, they showed higher levels of phosphorylated myosin light chain — known to be important for actin contraction — on actin bundles. As focal adhesion size is known to be proportional to cytoskeletal tension, the authors concluded that integrin-mediated changes in cytoskeletal tension were the key to driving cells apart.

To further examine how substrate-generated tension can alter cell-cell adhesions, HGF-induced scattering on substrates of different rigidity was analysed. In agreement with previous findings, decreasing substrate rigidity decreased the size of focal adhesions and scattering, further proving that tension generated through ECM-integrin mechanotransduction can disrupt cell-cell contacts.

Together these findings indicate that HGF treatment first stimulates integrin-dependent contraction of the actin cytoskeleton and that the physical breakdown of cadherins can then facilitate cell motility. It will be interesting to determine whether the same sequence of events takes place in vivo, during EMT or tumour metastasis.

Author: Monica Hoyos-Flight