Abstract
At the initial stage of carcinogenesis single mutated cells appear within an epithelium. Mammalian in vitro experiments show that potentially cancerous cells undergo live apical extrusion from normal monolayers. However, the mechanism underlying this process in vivo remains poorly understood. Mosaic expression of the oncogene vSrc in a simple epithelium of the early zebrafish embryo results in extrusion of transformed cells. Here we find that during extrusion components of the cytokinetic ring are recruited to adherens junctions of transformed cells, forming a misoriented pseudo-cytokinetic ring. As the ring constricts, it separates the basal from the apical part of the cell releasing both from the epithelium. This process requires cell cycle progression and occurs immediately after vSrc-transformed cell enters mitosis. To achieve extrusion, vSrc coordinates cell cycle progression, junctional integrity, cell survival and apicobasal polarity. Without vSrc, modulating these cellular processes reconstitutes vSrc-like extrusion, confirming their sufficiency for this process.
Highlights
At the initial stage of carcinogenesis single mutated cells appear within an epithelium
In the case of vSrctransformed cells, myosin activity regulated by myosin light chain kinase (MLCK) and Rho kinase (ROCK) as well as focal adhesion kinase (FAK) drive basal relocation of adherens junctions followed by apical extrusion[6]
We previously showed that when the oncogene vSrc was mosaically expressed in the enveloping layer (EVL), transformed cells were apically extruded[6] (Fig. 1b, Supplementary Movie 1)
Summary
At the initial stage of carcinogenesis single mutated cells appear within an epithelium. Mosaic expression of the oncogene vSrc in a simple epithelium of the early zebrafish embryo results in extrusion of transformed cells. We created a double Krt[18] promoter (dKrt[18]; Supplementary Fig. 1A, B) resulting in constitutive expression of modulators of extrusion within the EVL This in vivo system allowed us to generate two discrete cell populations: transformed and normal cells in a differentiated homogenous tissue. This approach uncovered a novel mode of extrusion in which vSrc holds the cell in the G2 phase of the cell cycle until a misoriented pseudo-cytokinetic ring is formed and constricted in early mitosis, resulting in the cell leaving the epithelium
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