Abstract
In this article, we explore a non-canonical form of collective cell migration, displayed by the metastatic murine mammary carcinoma cell line 4T1. We show here that in sparsely plated 4T1 cells, E-cadherin levels are moderately reduced (~50%), leading to the development of collective migration, whereby cells translocate in loose clusters, interconnected by thin membrane tethers. Knocking down E-cadherin blocked tether formation in these cells, leading to enhancement of migration rate and, at the same time, to suppression of lung metastases formation in vivo, and inhibition of infiltration into fibroblast monolayers ex vivo. These findings suggest that the moderate E-cadherin levels present in wild-type 4T1 cells play a key role in promoting cancer invasion and metastasis.
Highlights
Cancer invasion and metastasis are highly versatile processes, regulated at multiple levels, and characterized by several basic forms of cell migration[1]
Among other cell types tested, the highest levels of persistent migratory activity were seen in H1299 cells, which primarily migrated as single cells, and exhibited a broad range of largely dispersed cell-to-cell spacings, and 4T1 cells, which displayed a unique form of collective cell migration
We address the involvement of a non-canonical form of collective migration, whereby invading cancer cells move, while remaining loosely inter-connected by E-cadherin-mediated membrane tethers
Summary
Cancer invasion and metastasis are highly versatile processes, regulated at multiple levels, and characterized by several basic forms of cell migration[1]. The former mechanism is at work mainly in primary, undifferentiated carcinomas, and thought to be associated with a stable, “EMT-stemness” state[14], whereas environmentally-induced EMT is often a transient process, enabling the cells to re-acquire epithelial properties following mesenchymal-epithelial transition (MET)[9,12,14,15] Collective migration is another hallmark of invasive epithelial cancers, characterized by the capacity of cancer cells assemblies, interconnected by stable cell-cell junctions (mostly cadherin-mediated adherens-type junctions), to move through the ECM together, while maintaining their cell-cell connections[2,3,4,6]. Small cell clusters to dislodge from the primary tumor, penetrate into blood vessels or lymphatics, and extravasate in distant organs[1,9,12,13,19]
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