The majority of human carcinomas show loss of epithelial apical-basal polarity during the progression from benign to invasive carcinoma. Apical-basal polarity is often regarded as a gatekeeper against tumour development and metastasis. Epithelial-Mesenchymal Transition (EMT) provides stationary carcinoma cells the ability to invade and disseminate during metastasis. Although loss of epithelial cell polarity is an early step during the EMT process, polarity is largely thought to be a passive recipient of the EMT-inducing signals to decrease epithelial characteristics. Very little is known whether apical-basal polarity could directly impinge on the EMT transcription factors to function as feedback mechanisms to control EMT progression during tumor metastasis. This proposal focuses on understanding the mechanism by which apical-basal polarity regulatory machinery directly functions as a critical checkpoint of EMT to block tumor invasion and metastasis. Using mouse and human epithelial 3D organoid cultures with intact apical-basal polarity, we aim to 1) To elucidate the molecular mechanism by which apical-basal polarity blocks EMT and invasion; 2) To understand how the PAR polarity complex regulates EMT transcription factors to inhibit EMT; 3) To determine the involvement of the apical-basal polarity/EMT pathway in invasion and metastasis in vivo and in human breast cancer progression.
The proposed research aims to determine how apical-basal polarity regulates the EMT transcription factors to inhibit tumor invasion and metastasis. We believe that this work could uncover a novel regulatory machinery of tumor invasion and provide new targets for anti-metastasis therapy.
