Abstract

Epithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2–β-catenin–E-cadherin ternary complex and indirectly by inhibiting β-catenin’s N-terminal phosphorylation to stabilize the β-catenin–E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis.

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Acknowledgements

This work was supported mainly by the Ludwig Institute for Cancer Research Ltd (X.L.), and in part by the International Cooperation and Exchange Project of the National Natural Science Foundation of China (Y.G. and X.L.). Y.G. and J. Zhao are also supported by the National Basic Research Program of China (973 Program: 2010CB945600 and 2010CB833600). Y.W. is supported by the Medical Research Council (MR/J000930/1). S.S., J.R.L., M.S.S. and N.R.S. are funded by Cancer Research UK (grant number C5255/A12678). We thank K. Bryon-Dodd, G. Sutendra, P. Miller, M. White, L. Buti and C. Goding for critical reading of the manuscript. We are grateful to S. Shirasawa for providing HKe3 cells, F. Miller and S. Santner for the 4T1 and MCF10A series of breast cancer cell lines and Y. Fujita for the E-cadherin–Myc construct.

Author information

Author notes

    • Yihua Wang
    •  & Fangfang Bu

    These authors contributed equally to this work.

    • Christophe Royer

    Present address: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Affiliations

  1. Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK

    • Yihua Wang
    • , Christophe Royer
    • , Victoria Salter
    • , Florian Fritzsche
    • , Casmir Turnquist
    • , Sofia Koch
    • , Jaroslav Zak
    • , Shan Zhong
    • , Patricia A. Olofsen
    •  & Xin Lu
  2. International Joint Cancer Institute & Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China

    • Fangfang Bu
    • , Jian Zhao
    • , Xin Tong
    •  & Yajun Guo
  3. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China

    • Fangfang Bu
    • , Jian Zhao
    • , Xin Tong
    •  & Yajun Guo
  4. Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK

    • Sébastien Serres
    • , James R. Larkin
    • , Manuel Sarmiento Soto
    •  & Nicola R. Sibson
  5. Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland

    • Florian Fritzsche
    •  & Holger Moch
  6. Guangxi Cancer Hospital, Guangxi Medical University, Guangxi 530021, China

    • Guobin Wu
    •  & Anmin Liang
  7. Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields London WC2A 3LY, UK

    • David C. Hancock
    •  & Julian Downward
  8. Centre for Pathology, St Mary’s Hospital, Imperial College, London W2 1NY, UK

    • Robert D. Goldin

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Contributions

X.L. and Y.G. coordinated and supervised the project and designed the experiments together with Y.W. and F.B.; Y.W. carried out most of the experiments, analysed data and wrote the paper with X.L.; F.B. carried out experiments and analysed data for Figs 3d, 6d, e, 7a, b, 8a–c and Supplementary Figs 6c, d, 8a; C.R. carried out experiments for Fig. 5f, g and Supplementary Figs 2k, 5b–d, f, g; S.S., J.R.L., M.S.S. and N.R.S. designed, carried out experiments and analysed data with Y.W. for Fig. 7c–e and Supplementary Fig. 7b; V.S. and F.F. carried out immunohistochemistry in breast cancer tissue microarrays designed by H.M. and analysed data for Fig. 8d, e and Supplementary Fig. 8b; C.T. carried out experiments for Fig. 1b and Supplementary Fig. 1a; S.K. carried out experiments for Fig. 1c; J. Zak and S.Z. provided materials for Supplementary Fig. 1b, c; G.W. and A.L. provided the human HCC samples; P.A.O. carried out some experiments related to this project; D.C.H. and J.D. provided HKe3–ER:HRASV12 and MCF10A–ER:HRASV12 cell lines; R.D.G. provided pathological advice; J. Zhao designed and analysed the experiments of HCC with F.B.; X.T. carried out experiments and analysed data with F.B. for Fig. 8a–c and Supplementary Fig. 8a.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yajun Guo or Xin Lu.

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https://doi.org/10.1038/ncb3050

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