Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation.

Abstract

Loss of apical-basal polarity and activation of Epithelial-Mesenchymal Transition (EMT) both contribute to carcinoma progression and metastasis. Here, we report that apical-basal polarity inhibits EMT to suppress metastatic dissemination. Using mouse and human epithelial 3D organoid cultures, we show that the PAR/atypical protein kinase C (aPKC) polarity complex inhibits EMT and invasion by promoting degradation of SNAIL family protein SNAI1. Under intact apical-basal polarity, aPKC kinases phosphorylate SNAI1 on S249, leading to protein degradation. Loss of apical-basal polarity prevents aPKC-mediated SNAI1 phosphorylation and stabilizes SNAI1 protein to promote EMT and invasion. In human breast tumour xenografts, inhibition of the PAR complex-mediated SNAI1 degradation mechanism promotes tumour invasion and metastasis. Analyses of human breast tissue samples reveal negative correlations between PAR3 and SNAI1 protein levels. Our results demonstrate that apical-basal polarity functions as a critical checkpoint of EMT to precisely control epithelial-mesenchymal plasticity during tumour metastasis.