Article

Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1

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Abstract

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP–RAC1–JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+–CaMKII–NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

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Acknowledgements

We thank L. Li at SIBS for providing the TOP/FOPFLASH, ΔN-CTNNB1 and ΔC-LEF1 constructs; D. Xie at SIBS for providing the ΔN-TCF4 construct; Y. Xiao at SIBS for providing the RELA construct; M. Liu at SIBS for providing the PTGS2 construct; and X. Miao, H. Zhang, S Yan and P. Zhou at the Institute of Health Sciences core facilities for technical support. G.H. was funded by the National Natural Science Foundation of China (81430070, 81661148048, 31371409), the Chinese Academy of Sciences (QYZDB-SSW-SMC013, XDA12050101), the Ministry of Science and Technology of China (2013CB910904) and the Science and Technology Commission of Shanghai Municipality (14431900800).

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Affiliations

  1. The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China

    • Xueqian Zhuang
    • , Hao Zhang
    • , Xiaoxun Li
    • , Min Cong
    • , Fangli Peng
    • , Jingyi Yu
    • , Xue Zhang
    •  & Guohong Hu
  2. Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan 250012, China

    • Xiaoyan Li
    •  & Qifeng Yang

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Contributions

G.H. supervised the work. X.Zhuang and G.H. designed the experiments and drafted the manuscript. X.Zhuang, H.Z., M.C., F.P., J.Y. and X.Zhang performed the experiments. X.L. and Q.Y. contributed in clinical sample collection and analysis. Q.Y. helped design the experiments. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Qifeng Yang or Guohong Hu.

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