Matrix Stiffness Regulates Chemosensitivity, Stemness
Characteristics, and Autophagy in Breast Cancer Cells
Posted on 2020-06-26 - 15:37
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.
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Li, Yan; Randriantsilefisoa, Rotsiniaina; Chen, Jie; Cuellar-Camacho, Jose Luis; Liang, Wanjun; Li, Wenzhong (2020). Matrix Stiffness Regulates Chemosensitivity, Stemness
Characteristics, and Autophagy in Breast Cancer Cells. ACS Publications. Collection. https://doi.org/10.1021/acsabm.0c00448