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.
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 Labori, Inger 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
Nature Cell Biology 17, 816–826 (2015) doi:10.1038/ncb3169
Received 05 August 2014| Accepted 26 March 2015 | Published online 18 May 2015