Letter | Published:

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Nature volume 522, pages 106110 (04 June 2015) | Download Citation

Abstract

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia1. Tumour-secreted proteins play a crucial role in these interactions2,3,4,5 and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable6. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality6,7. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.

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Acknowledgements

We thank the animal welfare staff at the Institute of Cancer Research and Biocentre (University of Copenhagen); the Bone Analysis Laboratory (The University of Sheffield); M. Smid, J. W. M. Martens and J. A. Foekens (Erasmus MC Cancer Institute, Rotterdam, The Netherlands) for in-depth patient data analyses; and A. J. Giaccia and members of our laboratories for comments. This research was supported by funding from Cancer Research UK (C107/A10433) (T.R.C., D.B., G.L.J.T.E.), the Biotech Research and Innovation Centre (BRIC, University of Copenhagen) (T.R.C.), The University of Sheffield (A.G., I.D.H.), National Institute for Health Research Sheffield Clinical Research Facility (A.G.), Breast Cancer Campaign (#2012MayPR086) (A.G., R.M.H.R.), and the Danish Cancer Society (R56-A2971-12-S2) (A.M.H.). Experiments in the laboratory of R.L. were funded by The Lundbeck Foundation and the work was supported by the Velux Foundations (VKR)-funded Instrument Center for Systems Proteomics (VKR 022758). L.P. and J.T.E. are supported by a Hallas Møller Stipendum from the Novo Nordisk Foundation.

Author information

Author notes

    • Alison Gartland
    •  & Janine T. Erler

    These authors contributed equally to this work.

Affiliations

  1. Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark

    • Thomas R. Cox
    • , Lara Perryman
    • , Anette M. Høye
    • , Rune Linding
    •  & Janine T. Erler
  2. Hypoxia and Metastasis Team, Cancer Research UK Tumour Cell Signalling Unit, The Institute of Cancer Research, London SW3 6JB, UK

    • Thomas R. Cox
    • , Demelza Bird
    • , Georgina Lang
    •  & Janine T. Erler
  3. The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK

    • Robin M. H. Rumney
    • , Ankita Agrawal
    • , Norain Ab Latif
    • , Hamish Forrest
    • , Holly R. Evans
    • , Iain D. Huggins
    •  & Alison Gartland
  4. Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), Lyngby, DK-2800, Denmark

    • Erwin M. Schoof
    •  & Rune Linding

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Contributions

J.T.E. and A.G. conceived the project, assisted by T.R.C. T.R.C., A.G. and J.T.E. designed the experiments. T.R.C., A.G. and R.M.H.R. performed the in vivo and in vitro experiments and analysed the data assisted by L.P., A.H., A.A., D.B., N.A.L., H.F., H.R.E., I.D.H. and G.L. T.R.C. and E.M.S. designed and performed the mass spectrometry and proteomics experiments and analysis, supervised by R.L. T.R.C. wrote and edited the paper, assisted by A.G., J.T.E., R.L. and R.M.H.R.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alison Gartland or Janine T. Erler.

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    Supplementary Information

    This file contains Supplementary Expression data.

  2. 2.

    Supplementary Information

    This file contains full scans of Western blots.

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DOI

https://doi.org/10.1038/nature14492

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