Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Bruno Costa-Silva, Nicole M. Aiello, Allyson J. Ocean, Swarnima Singh, Haiying Zhang, Basant Kumar Thakur, Annette Becker, Ayuko Hoshino, Milica Tešić Mark, Henrik Molina, Jenny Xiang, Tuo Zhang, Till Martin Theilen, Guillermo García-Santos, Caitlin Williams, Yonathan Ararso, Yujie Huang, Gonçalo Rodrigues, Tang Long Shen, Knut Jørgen LaboriInger Marie Bowitz Lothe, Elin H. Kure, Jonathan Hernandez, Alexandre Doussot, Saya H. Ebbesen, Paul M. Grandgenett, Michael A. Hollingsworth, Maneesh Jain, Kavita Mallya, Surinder K. Batra, William R. Jarnagin, Robert E. Schwartz, Irina Matei, Héctor Peinado, Ben Z. Stanger, Jacqueline Bromberg, David Lyden

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882 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)816-826
Number of pages11
JournalNature Cell Biology
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2015

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Costa-Silva, B., Aiello, N. M., Ocean, A. J., Singh, S., Zhang, H., Thakur, B. K., Becker, A., Hoshino, A., Mark, M. T., Molina, H., Xiang, J., Zhang, T., Theilen, T. M., García-Santos, G., Williams, C., Ararso, Y., Huang, Y., Rodrigues, G., Shen, T. L., ... Lyden, D. (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology, 17(6), 816-826. https://doi.org/10.1038/ncb3169