N-cadherin-mediated cell–cell adhesion promotes cell migration in a three-dimensional matrix

Abstract

SummaryCancer cells that originate from epithelial tissues typically lose epithelial specific cell-cell junctions, but these transformed cells are not devoid of cell-cell adhesion proteins. Using hepatocyte-growth-factor-treated MDCK cells that underwent a complete epithelial-tomesenchymal transition, we analyzed cell-cell adhesion between these highly invasive transformed epithelial cells in a threedimensional (3D) collagen matrix. In a 3D matrix, these transformed cells formed elongated multicellular chains, and migrated faster and more persistently than single cells in isolation. In addition, the cell clusters were enriched with stress-fiber-like actin bundles that provided contractile forces. N-cadherin-knockdown cells failed to form cell-cell junctions or migrate, and the expression of the Ncadherin cytoplasmic or extracellular domain partially rescued the knockdown phenotype. By contrast, the expression of N-cadherina-catenin chimera rescued the knockdown phenotype, but individual cells within the cell clusters were less mobile. Together, our findings suggest that a dynamic N-cadherin and actin linkage is required for efficient 3D collective migration.

Modes of cancer cell invasion and the role of the microenvironment

“…Cells with mesenchymal morphologies can most readily switch between singlecell, streaming and collective migration modes. For example, in hepatocyte growth factor-treated MDCK cells, which have a mesenchymal phenotype, upregulation of N-cadherin activity can promote a switch from individual to collective cell migration [8].…”

p53 regulates cytoskeleton remodeling to suppress tumor progression

“…Dynamic N-cadherin-actin linkage has been shown to facilitate efficient collective cell invasion in 3D matrices [36]. N-cadherin mediates the formation of actin bundles; although, these differ from the stress fibers that form on stiff 2D substrates.…”

The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

“…N-cadherin can also play an essential role in collective migration. 129 Cells grown in a three-dimensional environment have been shown to establish focal adhesion differently compared with cells grown in a two-dimensional environment such as on plastic, which allows for the possibility that cell-cell adhesion could also be affected. 130,131 A three-dimensional environment, in which the cells were embedded in an extracellular matrix rather than grown on plastic, was required for the establishment of Ncadherin-mediated cell-cell adhesion after EMT hinting at matrixdependent cues, such as stiffness of the matrix, which have been demonstrated to affect cell migration and invasion (see below).…”