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Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion

  • Fan, Yao1, 2
  • Jalali, Aydin2
  • Chen, Andy2
  • Zhao, Xinyu2, 3
  • Liu, Shengzhi2
  • Teli, Meghana2
  • Guo, Yunxia1, 2
  • Li, Fangjia2
  • Li, Junrui4
  • Siegel, Amanda2
  • Yang, Lianxiang4
  • Liu, Jing2
  • Na, Sungsoo2
  • Agarwal, Mangilal2
  • Robling, Alexander G.5, 5
  • Nakshatri, Harikrishna5
  • Li, Bai-Yan1
  • Yokota, Hiroki1, 2, 4, 2, 5, 5
  • 1 Harbin Medical University, Harbin, 150081, China , Harbin (China)
  • 2 Indiana University Purdue University Indianapolis, Indianapolis, IN, 46202, USA , Indianapolis (United States)
  • 3 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China , Beijing (China)
  • 4 Oakland University, Rochester, MI, 48309, USA , Rochester (United States)
  • 5 Indiana University School of Medicine, Indianapolis, IN, 46202, USA , Indianapolis (United States)
Published Article
Bone Research
Nature Publishing Group UK
Publication Date
Feb 14, 2020
DOI: 10.1038/s41413-020-0083-6
Springer Nature


Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumor-induced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGFβ levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumor-osteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment.

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