E-cadherin is a structuring component of invadopodia in pancreatic cancer

Abstract

Graphical abstract BackgroundThe appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. However, the molecular mechanism and potential roles of E-cadherin in cancer cell invasion stay unexplored. MethodsWe used models of E/M hybrid cell lines, tissues sections and patient-derived xenografts from a multi-center clinical trial. E-cadherin involvement in invadopodia formation was assessed using a gelatin-FITC degradation assay. Mechanistic studies were performed by using proteomic analysis, siRNA strategy and proximity ligation assay. ResultsWe showed that E-cadherin is a critical component of invadopodia. This unexpected localization results from a synergistic trafficking of E-cadherin and MT1-MMP through Rab vesicle-dependent pathway. Modulation of E-cadherin expression or activation impacted invadopodia formation. Moreover, colocalization of E-cadherin and Actin in [-]ring structures|| as precursor of invadopodia reveals that E-cadherin is required for invadopodia structuration. ConclusionE-cadherin, initially localized in the adherens junctions could be recycled to nascent invadopodia where it will interact with several components such as Arp2/3, Cortactin or MT1-MMP. The trans-adhesive properties of E-cadherin are therefore essential for structuring invadopodia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/332783v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@13b08e8org.highwire.dtl.DTLVardef@c5d19eorg.highwire.dtl.DTLVardef@14511cforg.highwire.dtl.DTLVardef@19436eb_HPS_FORMAT_FIGEXP M_FIG C_FIG