• A Corrigendum to this article was published on 06 July 2016

Abstract

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression1,2,3,4, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

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Gene Expression Omnibus

Data deposits

Microarray data are available in the GEO database under accession number GSE57445.

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Acknowledgements

We thank D. Altieri, R. Marais, Z. Ronai, M. McMahon, and B. Vogelstein for comments on the manuscript. We thank R. Somasundaram for advice on immune analyses, M. Herlyn for the WM cell lines, and G. Bollag for PLX4720. We also thank R. Delgiacco, D. Gourevitch, F. Keeney, and D. Schultz. We thank A. Dias-Wanigasekera, E. Gaddy, and M. Ha for technical assistance, and R. Locke for editing the manuscript. This work was supported in part by funds from the Intramural Program of the National Institute on Aging, Baltimore, Maryland (N.M., K.G.B., R.M., W.H.W., L.F.), The Harry J. Lloyd Foundation (K.M., A.T.W.), P01 CA 114046-06 (A.T.W., Q.L.), T32 CA 9171-36 (M.R.W., C.H.K.), an ACS-IRG award (A.T.W.), the Melanoma Research Foundation (A.T.W.), and RO1 CA174746-01 (A.T.W., A.K.). Core facilities at the Wistar are supported by Cancer Center Support Grant P30 CA010815.

Author information

Affiliations

  1. The Wistar Institute, Philadelphia, Pennsylvania 19104, USA

    • Amanpreet Kaur
    • , Marie R. Webster
    • , Katie Marchbank
    • , Reeti Behera
    • , Abibatou Ndoye
    • , Curtis H. Kugel
    • , Vanessa M. Dang
    • , Jessica Appleton
    • , Michael P. O’Connell
    • , Alexander A. Valiga
    • , Andrew V. Kossenkov
    • , Hsin-Yao Tang
    • , Xiangfan Yin
    • , Katherine M. Aird
    • , Rugang Zhang
    • , Qin Liu
    • , David W. Speicher
    •  & Ashani T. Weeraratna
  2. University of the Sciences, Philadelphia, Pennsylvania 19104, USA

    • Amanpreet Kaur
  3. Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland

    • Phil Cheng
  4. The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA

    • Rachel Morissette
    • , Nazli B. McDonnell
    • , Luigi Ferrucci
    • , William H. Wood
    • , Elin Lehrmann
    •  & Kevin G. Becker
  5. Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA

    • Katrina Meeth
    •  & Marcus Bosenberg
  6. Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA

    • Keith T. Flaherty
    •  & Dennie T. Frederick
  7. Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jennifer A. Wargo
    • , Zachary A. Cooper
    • , Michael T. Tetzlaff
    •  & Courtney Hudgens
  8. Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Xiaowei Xu
    • , Edmund Bartlett
    •  & Giorgos Karakousis
  9. Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA

    • Zeynep Eroglu
  10. Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA

    • Roger S. Lo
    •  & Antoni Ribas
  11. Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia

    • Matthew Chan
  12. Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia

    • Alexander M. Menzies
    •  & Georgina V. Long
  13. Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA

    • Douglas B. Johnson
    •  & Jeffrey Sosman
  14. Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany

    • Bastian Schilling
    •  & Dirk Schadendorf
  15. German Cancer Consortium (DKTK), Heidelberg 45127, Germany

    • Bastian Schilling
    •  & Dirk Schadendorf

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Contributions

A.T.W. conceived and designed the project. A.T.W. and A.K. designed and supervised the experiments. A.K., M.R.W., K.M., R.B., A.N., C.H.K., V.M.D., J.A., M.P.O., P.C., A.A.V., W.H.W., E.L., and K.M.A. performed the experiments. A.T.W., A.K., A.V.K., H.Y.T., X.Y., E.L., Z.E., K.G.B., R.Z., X.X., Q.L., and D.W.S. analysed the experimental data. A.T.W., A.K., and Q.L. designed and supervised data analysis and statistical analysis. M.B., A.R., D.S., J.S., B.S., R.S.L., M.C., A.M.M., G.V.L., D.B.J., R.M., N.B.M., L.F., K.M., K.T.F., D.T.F., J.A.W., Z.A.C., M.T.T., C.H., E.B., and G.K. performed data collection and provided anonymized patient data and samples and reagents. A.T.W. and A.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

K.T.F. is a consultant to GlaxoSmithKline, Roche, and Novartis; G.V.L. is a consultant to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MSD, Novartis, and Roche; J.A.W. is a consultant to Roche and GlaxoSmithKline. We do not believe these relationships have any direct impact on this work.

Corresponding author

Correspondence to Ashani T. Weeraratna.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure

    This file contains the raw data for Figures 2a, 2g, 3a, 3e, 4f, 4g, 5b and Extended Data Figures 6b, 6c, 8e, 10b, 10c.

  2. 2.

    Supplementary Tables

    This file is a compilation of tables outlining the antibodies, vectors and primers used, and the sources from which they came. Extended statistics for patient data, as well as patient information are also included.

About this article

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DOI

https://doi.org/10.1038/nature17392

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