ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion

Tumor invasion can be induced by changes in gene expression that alter cell phenotype. The transcription factor Delta Np63 alpha promotes basal-like breast cancer (BLBC) migration by inducing the expression of the mesenchymal genes Slug and Axl, which confers cells with a hybrid epithelial/mesenchymal state. However, the extent of the Delta Np63 alpha regulated genes that support invasive behavior is not known. Here, using gene expression analysis, ChIP-seq, and functional testing, we find that Delta Np63 alpha promotes BLBC motility by inducing the expression of the atypical cadherin FAT2, the vesicular binding protein SNCA, the carbonic anhydrase CA12, the lipid binding protein CPNE8 and the kinase NEK1, along with Slug and Axl. Notably, lung squamous cell carcinoma migration also required Delta Np63 alpha dependent FAT2 and Slug expression, demonstrating that Delta Np63 alpha promotes migration in multiple tumor types by inducing mesenchymal and non-mesenchymal genes. Delta Np63 alpha activation of FAT2 and Slug influenced E-cadherin localization to cell-cell contacts, which can restrict spontaneous cell movement. Moreover, live-imaging of spheroids in organotypic culture demonstrated that Delta Np63 alpha, FAT2 and Slug were essential for the extension of cellular protrusions that initiate collective invasion. Importantly, Delta Np63 alpha is coexpressed with FAT2 and Slug in patient tumors and the elevated expression of Delta Np63 alpha, FAT2 and Slug correlated with poor patient outcome. Together, these results reveal how Delta Np63 alpha promotes cell migration by directly inducing the expression of a cohort of genes with distinct cellular functions and suggest that FAT2 is a new regulator of collective invasion that may influence patient outcome.