The SRC-induced mesenchymal state in late-stage colon cancer cells.
One major function of elevated Src kinase in epithelial cancer cells is to drive adhesion changes that are associated with the mesenchymal transition and metastasis. Here we review recent work that describes Src-induced shape changes, and the mechanisms involved, in cells derived from a model of colon cancer metastasis. Src activity in these cells is associated with formation and dynamic regulation of integrin adhesions and disorganization of E-cadherin-dependent cell-cell contacts. Furthermore, Src-induced deregulation of E-cadherin requires integrin signalling, demonstrating a complex interdependence between integrin- and cadherin-associated adhesion changes induced by Src. The integrin-induced signals that co-operate with Src to cause deregulation of cadherin-dependent cell-cell contacts include activation of the MEK/ERK and MLCK/myosin activities. Inhibition of this pathway suppresses integrin complexes formed on fibronectin, while promoting E-cadherin redistribution to sites of cell-cell contacts. Also, in embryonic fibroblasts that express N-cadherin (which is normally diffusely cytoplasmic as these cells maintain a fibroblastic morphology) suppressing integrin signalling and inhibiting the MEK/ERK/MLCK/myosin pathway relocalizes N-cadherin to cell-cell contacts. Our recent data therefore imply an important, and perhaps general, role for spatially controlled contractility in suppressing normal cadherin localization and inducing a mesenchymal-like phenotype.
Avizienyte
Egle
E
Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow, UK.
Brunton
Valerie G
VG
Fincham
Valerie J
VJ
Frame
Margaret C
MC
D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D048429:Cell Size; D003110:Colonic Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium / Q000196:embryology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000378:metabolism; D018715:Microscopy, Video; D008954:Models, Biological; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D015820:Cadherins; D016023:Integrins; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D009218:Myosins