Actin cytoskeletal control during epithelial to mesenchymal transition: focus on the pancreas and intestinal tract

Abstract

The formation of epithelial tissues allows organisms to specialise and form tissues with diverse functions and compartmentalised environments. The tight controls on cell growth and migration required to maintain epithelia can present problems such as the development and spread of cancer when normal pathways are disrupted. By attaining a deeper understanding of how cell migration is suppressed to maintain the epithelial organisation and how it is reactivated when epithelial tissues become mesenchymal, new insights into both cancer and development can be gained. Here we discuss recent developments in our understanding of epithelial and mesenchymal regulation of the actin cytoskeleton in normal and cancerous tissue, with a focus on the pancreas and intestinal tract.

Figure 1

Involvement of actin cytoskeletal reorganisation in EMT. Epithelial cells make tight junctions (TJ, red) that act as a permeability barrier between the outside world and the tissue and adherens juncions (AJ) that provide mechanical stability and strength by connections with the actin cytoskeleton and the transmembrane cadherin proteins. E-cadherins (green) are major scaffold proteins controlling adherens junction integrity and direct links between E-cadherins and actin nucleating proteins, such as WRC (light blue) and Arp2/3 complex (multicoloured) provide a basis for sequestering the actin nucleation machinery when cells are non-motile and also for harnessing actin nucleation to provide actin cytoskeletal scaffolding for tissue integrity. N-WASP (purple) acts with WIRE (not shown) to stabilise and bundle cortical actin filaments (Wu et al, 2014). Cortactin (orange) is a scaffold, binding both N-WASP and E-cadherin to recruit ARP2/3 and WRC to adherens junctions. EMT can be driven by a number of signalling pathways (purple boxes, see text for references) that result in the activation of transcriptional programmes and alternative splicing. In mesenchymal cells, E-cadherin is lost and the actin cytoskeleton undergoes a number of changes, resulting in a shift of actin and its regulatory proteins and complexes from the cortex towards the leading edge of migrating cells, where they form lamellipodia. A specialised mesenchymal actin bundling protein, fascin, organises actin filaments at sites of filopodia and is also recruited to invadopodia, the invasive protrusions of cancer cells, along with Arp2/3 complex, cortactin and N-WASP. These changes are accompanied by the expression of mesenchymal markers such as N-cadherin, vimentin and fibronectin and a change in cell polarity (from the apico–basal polarity in epithelial cells to the front–back polarity in mesenchymal cells).