Abstract

Bone metastases remain a serious health concern because of limited therapeutic options. Here, we report that crosstalk between ROR1–HER3 and the Hippo–YAP pathway promotes breast cancer bone metastasis in a long noncoding RNA-dependent fashion. Mechanistically, the orphan receptor tyrosine kinase ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307, following neuregulin stimulation, independently of other ErbB family members. p-HER3 Tyr1307 recruits the LLGL2–MAYA–NSUN6 RNA–protein complex to methylate Hippo/MST1 at Lys59. This methylation leads to MST1 inactivation and activation of YAP target genes in tumour cells, which elicits osteoclast differentiation and bone metastasis. Furthermore, increased ROR1, p-HER3 Tyr1307 and MAYA levels correlate with tumour metastasis and unfavourable outcomes. Our data provide insights into the mechanistic regulation and linkage of the ROR1–HER3 and Hippo–YAP pathway in a cancer-specific context, and also imply valuable therapeutic targets for bone metastasis and possible therapy-resistant tumours.

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Acknowledgements

We are grateful to J. Massague and X. Zhang for providing the MDA-MB-231 LM2 and BoM-1833 cell lines and to D. Yu for providing the MDA-MB-231-BRN and BT474-BRN cells. We thank D. Aten for assistance with figure presentation. This work was supported by National Institutes of Health Pathway to Independence Award (R00CA166527) and Cancer Prevention Research Institute of Texas First-time Faculty Recruitment Award (R1218) grants to L.Q.Y. and National Institutes of Health Pathway to Independence Award (R00DK094981) to C.R.L.

Author information

Author notes

    • Chunlai Li
    •  & Shouyu Wang

    These authors contributed equally to this work.

    • Shouyu Wang
    •  & Aifu Lin

    Present addresses: Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China (S.W.); College of Life Sciences, Zhejiang University, Hangzhou 310058, China (A.L.).

Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Chunlai Li
    • , Shouyu Wang
    • , Zhen Xing
    • , Aifu Lin
    • , Ke Liang
    • , Qingsong Hu
    • , Jun Yao
    • , Peter K. Park
    • , Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jian Song
    •  & Gary E. Gallick
  3. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Zhongyuan Chen
    •  & Han Liang
  4. Department of Statistics, Rice University, Houston, Texas 77030, USA

    • Zhongyuan Chen
  5. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • David H. Hawke
    •  & Han Liang
  6. Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China

    • Jianwei Zhou
  7. Department of Oncology, Yixing People’s Hospital, 75 Zhenguan Road, Yixing 214200, China

    • Yan Zhou
  8. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Shuxing Zhang
  9. The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  10. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan

    • Mien-Chie Hung
  11. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA

    • Leng Han
  12. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Liuqing Yang

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Contributions

C.L.L. and S.W. devised and performed most experiments. K.L., J.S. and G.E.G. helped with mouse intracardiac injections. A.L., Z.X. and Q.H. helped with biochemistry studies. D.H.H. performed mass spectrometry analysis. Clinical specimens were ascertained and processed by J.Z. and Y.Z. The histological staining and corresponding analysis were performed by K.L. P.K.P. assisted with manuscript drafting. J.Y., L.H., Z.C. and H.L. performed bioinformatics analysis. S.Z. and M.-C.H. contributed to discussion and data interpretation. L.Y. and C.R.L. initiated and supervised the project and wrote the paper with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chunru Lin or Liuqing Yang.

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https://doi.org/10.1038/ncb3464

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