Journal
NATURE CELL BIOLOGY
Volume 21, Issue 3, Pages 359-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0291-8
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Funding
- UCSD Cancer Centre Support Grant from the NCI [P30 CA23100]
- ACS [RSG-09-282-01-CSM]
- NCI [1RO1CA168689, 1R01CA174869, 1R01CA206880, 1R21CA191442]
- NIH [NIH R35 GM122523, NIH P01 DK054441]
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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 three-dimensional organoid cultures, we show that the PAR-atypical protein kinase C (aPKC) polarity complex inhibits EMT and invasion by promoting degradation of the SNAIL family protein SNAI1. Under intact apical-basal polarity, aPKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. Loss of apical-basal polarity prevents aPKC-mediated SNAI1 phosphorylation and stabilizes the 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.
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