The Regulation of Autophagy in YAP Mechanotransduction and Breast Cancer Metastasis

Abstract

Breast cancer metastasis of a variety of vital organs is a major cause of breast cancer mortality. Autophagy has a crucial role in the metastatic breast cancer progression. As a critical mechanotransducer in the Hippo signalling pathway, YAP regulates cell proliferation and promotes autophagy. Previous publications also demonstrated extracellular matrix could regulate the nucleo-cytoplasmic transport of YAP. However, how YAP signalling connects to the interplay of autophagy and mechanotransduction in breast cancer metastasis remains entirely unknown. Through rapamycin-induced autophagy on the metastatic triple negative breast cancer (TNBC) cells, we observed upregulated YAP transcriptional activity and YAP nuclear localization in TNBC. Thus, we reported that YAP nuclear localization regulates autophagy to promote TNBC metastasis. Culturing TNBC cells on PDMS plates with various matrix stiffness demonstrated that stiff matrix promoted the migration of metastatic breast cancer cells in a YAP-dependent mechanism. Therefore, we proposed that YAP mechanotransduction promotes the migration of metastatic breast cancer cells. Then, we advance in these directions by reporting autophagy-mediated YAP nuclear localization is regulated by the response to stiff matrix when TNBC cells were cultured on different matrix stiffness upon autophagy. In conclusion, we suggest autophagy and mechanotransduction mediates YAP nuclear localization together. These findings expand the unknown gap in the convergence of YAP mechanotransduction and autophagy in metastatic breast cancer. They suggest that metastatic breast cancer cells have the potential to exhibit different YAP signalling when they colonize on a secondary location with a distinct matrix stiffness from primary location. Our study further helped to understand YAP biology and the mechanism of breast cancer metastasis that will shed light on future YAP-targeting therapeutics for metastatic breast cancer.