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Metastasis is the main cause of cancer-related deaths. How a single oncogenic cell evolves within highly organized epithelium is still unknown. Here, we found that the overexpression of the protein kinase atypical protein kinase C (aPKCi), an oncogene, triggers basally oriented epithelial cell extrusion in vivo as a potential mechanism for early breast tumor cell invasion. We found that cell segregation is the first step required for basal extrusion of luminal cells and identify aPKCi and vinculin as regulators of cell segregation. We propose that asymmetric vinculin levels at the junction between normal and aPKCi+ cells trigger an increase in tension at these cell junctions. Moreover, we show that aPKCi+ cells acquire promigratory features, including increased vinculin levels and vinculin dynamics at the cell-substratum contacts. Overall, this study shows that a balance between cell contractility and cell-cell adhesion is crucial for promoting basally oriented cell extrusion, a mechanism for early breast cancer cell invasion. [ABSTRACT FROM AUTHOR]

Purse-string healing is driven by contraction of actin/myosin cables that span cells at wound edges, and it is the predominant mode of closing small round wounds in embryonic and some adult epithelia. Wounds can also heal by cell crawling, and my colleagues and I have shown previously that the presence of unconstrained, straight edges in sheets of epithelial cells is a sufficient signal to induce healing by crawling. Here, it is reported that the presence of highly concave edges, which are free or physically constrained by an inert material (agarose), is sufficient to induce formation of purse strings. It was determined that neither of the two types of healing required cell damage or other potential stimuli by using the particularly gentle procedure of introducing gaps by digesting agarose blocks imbedded in the cell sheets. Movement by crawling depends on signaling by the EGF receptor (EGFR); however, this was not required for purse-string contraction. A migrating epithelial cell sheet usually produces finger-like projections of crawling cells. The cells between fingers contain continuous actin cables, which were also determined to contain myosin IIA and exhibit additional characteristics of purse strings. When crawling was blocked by inhibition of EGFR signaling, the concave regions continued to move, suggesting that both mechanisms contribute to propel the sheets forward. Wounding epithelial cell sheets causes activation of the EGFR, which triggers movement by crawling. The EGFR was found to be activated only at straight and convex edges, which explains how both types of movement can coexist at leading epithelial edges. [ABSTRACT FROM AUTHOR]

Tissue patterning relies on cellular reorganization through the interplay between signaling pathways and mechanical stresses. Their integration and spatiotemporal coordination remain poorly understood. Here we investigate the mechanisms driving the dynamics of cell delamination, diversely deployed to extrude dead cells or specify distinct cell fates. We show that a local mechanical stimulus (subcellular laser perturbation) releases cellular prestress and triggers cell delamination in the amnioserosa during Drosophila dorsal closure, which, like spontaneous delamination, results in the rearrangement of nearest neighbors around the delaminating cell into a rosette. We demonstrate that a sequence of "emergent cytoskeletal polarities" in the nearest neighbors (directed myosin flows, lamellipodial growth, polarized actomyosin collars, microtubule asters), triggered by the mechanical stimulus and dependent on integrin adhesion, generate active stresses that drive delamination. We interpret these patterns in the language of active gels as asters formed by active force dipoles involving surface and body stresses generated by each cell and liken delamination to mechanical yielding that ensues when these stresses exceed a threshold. We suggest that differential contributions of adhesion, cytoskeletal, and external stresses must underlie differences in spatial pattern. [ABSTRACT FROM AUTHOR]