Modelling variability and heterogeneity of EMT scenarios highlights nuclear positioning and protrusions as main drivers of extrusion

Abstract

Epithelial-Mesenchymal Transition (EMT) is a key process in physiological and pathological settings (i.e. development, fibrosis, cancer). EMT is often presented as a linear sequence of events including (i) disassembly of cell-cell junctions, (ii) loss of epithelial polarity and (iii) reorganization of the cytoskeleton leading to basal extrusion from the epithelium. Once out, cells can adopt a migratory phenotype with a front-rear polarity and may additionally become invasive. While this stereotyped sequence can occur, many in vivo observations have challenged this notion. It is now accepted that there are multiple EMT scenarios and that cell populations implementing EMT are often heterogeneous. However, the relative importance of each EMT step towards extrusion is unclear. Similarly, the overall impact of variability and heterogeneity on the efficiency and directionality of cell extrusion has not been assessed. Here we used computational modelling of a pseudostratified epithelium to model multiple EMT-like scenarios. We confronted these in silico data to the EMT occurring during neural crest delamination. Overall, our simulated and biological data point to a key role of nuclear positioning and protrusive activity to generate timely basal extrusion of cells and suggest a non-linear model of EMT allowing multiple scenarios to co-exist.