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Polarity reversal during epithelial-to-mesenchymal transition

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Epithelial to mesenchymal transition (EMT) is a morphogenetic event that takes place during specific stages of embryo development and early stages of tumour dissemination. Proper tissue functions strongly depend on the establishment of cell polarity. Epithelial, non-motile cells establish an apico-basal polarity whereas mesenchymal, migrating cells display a front-rear polarity. Polarized distributions of cell-cell and cell-matrix adhesions direct the asymmetric spatial organization of cell internal compartments to establish cell polarity. Cell adhesions remodelling being central to EMT , we hypothesized it was coupled to polarity changes. We monitored centrosome positioning during EMT since it is a central regulator of cell polarity. Indeed, it defines microtubules network architecture and thereby orients internal traffic. First, we observed that EMT induction by TGF causes disorganization of cells in 3D epithelial cell cultures along with the loss of centrosome localization to apical side. To understand whether centrosome mislocalization was a driver of EMT or a consequence of cells disorganization, we used a minimal model of tissue comprising two cells whose positions were controlled on a micropattern. We found that nucleus-centrosome axis was preferentially orientated to the cell-cell junction in epithelial cell pair. Few hours following the addition of EMT inducers, the cells in the very early stages of EMT were detected to undergo polarity reversal by centrosome repositioning toward cell-ECM adhesions. This phenomenon was more pronounced under prolonged presence of EMT inducer over 3-5 days. This process could be confirmed in three different epithelial cell types. Centrosome repositioning could be reverted in epithelial and mesenchymal states by the modulation of the expression levels of Par3, which is a polarity complex protein localized to cell-cell junctions. In parallel, polarity reversal was associated with re-distribution of cell-cell and cell-ECM traction forces. Increase in traction forces compared to intercellular forces in mesenchymal cells seemed to prime them for scattering. Finally, we demonstrated that centrosome repositioning during EMT directly induces the scattering of mesenchymal cells with the help of dynamic surface coating to control cell release from micropatterns. Indeed centrosome repositioning was required for mesenchymal cell to separate and migrate away from each other. Preliminary observations in developing mouse mammary gland and early mouse embryo suggested polarity reversal was actually instrumental in physiological EMT . These findings demonstrate that upon onset of EMT , epithelial cells execute a polarity reversal program by centrosome repositioning which is necessary for the scattering of resulting mesenchymal cells.

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