Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells

  • Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165625. doi: 10.1016/j.bbadis.2019.165625.
Xiang Qin  1 ,  Xiaoying Lv  2 ,  Ping Li  2 ,  Rui Yang  2 ,  Qiong Xia  2 ,  Yu Chen  2 ,  Yueting Peng  2 ,  Li Li  1 ,  Shun Li  1 ,  Tingting Li  1 ,  Ying Jiang  1 ,  Hong Yang  1 ,  Chunhui Wu  1 ,  Chuan Zheng  3 ,  Jie Zhu  3 ,  Fengming You  3 ,  Heng Wang  4 ,  Jiong Chen  4 ,  Yiyao Liu  5
Affiliations
  • 1. Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China; Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
  • 2. Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
  • 3. Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China.
  • 4. State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, Jiangsu, PR China.
  • 5. Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China; Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China; Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: [email protected].
PMID: 31785406 DOI: 10.1016/j.bbadis.2019.165625
Abstract

One of the hallmarks of Cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast Cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast Cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast Cancer treatment delivery systems.

Keywords
Drug resistance; ILK; Matrix stiffness; Mechanotransduction; YAP.
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