Abstract

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

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Acknowledgements

We thank D. L. Bajor (Vonderheide laboratory, University of Pennsylvania) for the gift of the R6560B cells. We thank L. Bojmar for carefully reviewing the paper. We thank S. Rudchenko and M. Barbu-Stevanovic at the Hospital for Special Surgery Fannie E. Rippel Foundation Flow Cytometry Core Facility for expert flow cytometry. We are supported by grants from the Children’s Cancer and Blood Foundation (H.P., D.L.), Manning Foundation (D.L.), Hartwell Foundation (D.L.), Champalimaud Foundation (D.L.), Fundacao para a Ciencia e a Tecnologia (D.L.), Nancy C and Daniel P Paduano Foundation (H.P., D.L.), Mary Kay Foundation (D.L.), Pediatric Oncology Experimental Therapeutic Investigator Consortium (D.L.), James Paduano Foundation (D.L., H.P.), Melanoma Research Alliance (H.P.), Sohn Conference Foundation (H.P.), Beth Tortolani Foundation (D.L., J.B.), Malcolm Hewitt Weiner Foundation (D.L.), Jose Carreras Leukemia Foundation (B.K.T.), Theodore Rapp Foundation (D.L.), American Hellenic Educational Progressive Association 5th District Cancer Research Foundation (D.L.), Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), Breast Cancer Alliance (J.B.), and Manhasset Women’s Coalition Against Breast Cancer (J.B.).

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Affiliations

  1. Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA

    • Bruno Costa-Silva
    • , Swarnima Singh
    • , Haiying Zhang
    • , Basant Kumar Thakur
    • , Annette Becker
    • , Ayuko Hoshino
    • , Till-Martin Theilen
    • , Guillermo García-Santos
    • , Caitlin Williams
    • , Yonathan Ararso
    • , Yujie Huang
    • , Gonçalo Rodrigues
    • , Saya H. Ebbesen
    • , Irina Matei
    • , Héctor Peinado
    •  & David Lyden
  2. Gastroenterology Division, Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA

    • Nicole M. Aiello
    •  & Ben Z. Stanger
  3. Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York 10021, USA

    • Allyson J. Ocean
  4. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany

    • Basant Kumar Thakur
  5. Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA

    • Milica Tešić Mark
    •  & Henrik Molina
  6. Genomics Resources Core Facility, Weill Cornell Medical College, New York, New York 10021, USA

    • Jenny Xiang
    •  & Tuo Zhang
  7. Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal

    • Gonçalo Rodrigues
  8. Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan

    • Tang-Long Shen
  9. Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway

    • Knut Jørgen Labori
  10. Department of Pathology, Oslo University Hospital, Nydalen, Oslo 0424, Norway

    • Inger Marie Bowitz Lothe
  11. Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway

    • Inger Marie Bowitz Lothe
    •  & Elin H. Kure
  12. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Jonathan Hernandez
    • , Alexandre Doussot
    •  & William R. Jarnagin
  13. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA

    • Paul M. Grandgenett
    •  & Michael A. Hollingsworth
  14. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA

    • Maneesh Jain
    • , Kavita Mallya
    •  & Surinder K. Batra
  15. Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA

    • Robert E. Schwartz
  16. Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain

    • Héctor Peinado
  17. Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York 10065, USA

    • Jacqueline Bromberg
  18. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • David Lyden

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Contributions

B.C-S. developed the hypothesis, designed the experimental approach, performed experiments, analysed the data, coordinated the project and wrote the manuscript. N.M.A. conducted experiments. S.S., G.R. and T-L.S. performed immunostaining. H.Z. and Y.H. extracted RNA. B.K.T. and A.B. performed western blots. A.H., T-M.T., C.W. and Y.A. maintained mouse colonies. M.T.M. and H.M. performed proteomic analysis. J.X. and T.Z. processed samples and analysed RNA sequencing data. G.G-S. and C.W. processed human samples. P.M.G., M.A.H., K.J.L., I.M.B.L., E.H.K., A.J.O., J.H., A.D., M.J., K.M., S.K.B. and W.R.J. collected patient samples and managed clinical records. S.H.E. contributed to writing the manuscript. R.E.S., I.M., H.P. and B.Z.S. contributed to hypothesis generation, experimental design and data interpretation. J.B. coordinated the project and interpreted data. D.L. conceived the hypothesis, led the project, interpreted data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ben Z. Stanger or Jacqueline Bromberg or David Lyden.

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https://doi.org/10.1038/ncb3169

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