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Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S

Nature Cell Biology volume 16, pages 876888 (2014) | Download Citation

Abstract

Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour–stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood–brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.

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Acknowledgements

We thank K. Simpson and X. Chen for excellent technical support, and members of the J.A.J. laboratory for insightful discussion. We thank L. Akkari, O. Olson and D. Yan for reading the manuscript. We are grateful to P. Bos for advice on the BBB assays and experimental brain metastasis model. We thank the MSKCC Core Facilities of Genomics, Molecular Cytology, Small Animal Imaging and Monoclonal Antibody Production for technical assistance. We thank H. Chapman (UCSF) for providing cathepsin S KO mice. This research was supported by the following: US National Cancer Institute program grants of the Integrative Cancer Biology Program (CA148967; J.A.J., C.S.L.) and Tumour Microenvironment Network (CA126518; J.A.J., J.M.), the Health Research Science Board of New York, and the Alan and Sandra Gerry Metastasis Research Initiative (J.A.J.), Deutsche Forschungsgemeinschaft (SE2234/1-1; L.S.), US National Cancer Institute F31 fellowship CA167863 and Gerstner Sloan Kettering graduate program (R.L.B.), US National Cancer Institute F32 fellowship CA130329 (S.D.M.), and Canadian Institutes of Health Research (D.F.Q.).

Author information

Author notes

    • Robert L. Bowman
    •  & Steven D. Mason

    These authors contributed equally to this work.

Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Lisa Sevenich
    • , Robert L. Bowman
    • , Steven D. Mason
    • , Daniela F. Quail
    • , Benelita T. Elie
    • , Joan Massagué
    •  & Johanna A. Joyce
  2. Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Franck Rapaport
    •  & Christina S. Leslie
  3. Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Edi Brogi
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Priscilla K. Brastianos
    •  & William C. Hahn
  5. Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA

    • Priscilla K. Brastianos
  6. Virobay Inc., 1360 Willow Road, Menlo Park, California 94025, USA

    • Leslie J. Holsinger
  7. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Joan Massagué
    •  & Johanna A. Joyce
  8. Metastasis Research Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Joan Massagué
    •  & Johanna A. Joyce

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Contributions

L.S., S.D.M. and J.A.J. designed experiments. L.S., S.D.M., D.F.Q. and B.T.E. performed experiments and analysed data. R.L.B., F.R. and C.S.L. performed computational analyses. E.B., P.K.B., W.C.H., L.J.H. and J.M. provided patient samples or reagents. J.A.J., L.S. and R.L.B. wrote the manuscript. All authors edited or commented on the manuscript. J.A.J. conceived and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johanna A. Joyce.

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DOI

https://doi.org/10.1038/ncb3011

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