Matrix Stiffness Regulates Chemosensitivity, Stemness Characteristics, and Autophagy in Breast Cancer Cells.

Abstract

The biomechanical environment of natural or synthetic extracellular matrices (ECMs) is identified to play a considerable role in embryonic development in stem cell fate and also in cancer development and fibrotic diseases. However, rare evidence shows the impact of biomechanical signals such as ECM stiffness on cancer cell stemness and autophagy, which makes huge contributions to cancer and many developmental and physiological processes. Furthermore, the influence and mechanism of ECM stiffness on autophagy in cancer cells remains unclear. Herein, we employed fibronectin-coated polyacrylamide hydrogels as the substrates for culturing breast cancer cells. We found that a soft environment was beneficial for the maintenance of cancer stem cell (CSC) population in breast cancer cells, which likely led to aggravated chemoresistance. Conversely, nutritional deprivation-induced autophagy was elevated along with increasing matrix stiffness. In addition, we found that though the central regulator of mechanotransduction, the yes-associated protein, YAP, was beneficial for autophagy activation, unexpectedly, it was not the main cause of rigid substrate promoting autophagy. In contrast, the YAP was crucial for a compliant environment for maintaining breast cancer stem cells and promoting chemotherapeutic resistance. We also found that the Rho-ROCK-ERK signal pathway and actin cytoskeleton were essential for the regulation of autophagy by matrix stiffness. Taken together, our study showed the important influence of ECM stiffness on stemness and autophagy in breast cancer cells and revealed the possible signal pathway involved in the mechanotransduction in autophagy activation, which provides significant implications for the study of cancer progression and design of hydrogels for tissue engineering in clinical therapy.