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00925njm 22002777a 4500 dc Costa-Silva, Bruno author Aiello, Nicole M author Ocean, Allyson J author Singh, Swarnima author Zhang, Haiying author Thakur, Basant Kumar author Becker, Annette author Hoshino, Ayuko author Mark, Milica Tešić author Molina, Henrik author Xiang, Jenny author Zhang, Tuo author Theilen, Till-Martin author García-Santos, Guillermo author Williams, Caitlin author Ararso, Yonathan author Huang, Yujie author Rodrigues, Gonçalo author Shen, Tang-Long author Labori, Knut Jørgen author Lothe, Inger Marie Bowitz author Kure, Elin H author Hernandez, Jonathan author Doussot, Alexandre author Ebbesen, Saya H author Grandgenett, Paul M author Hollingsworth, Michael A author Jain, Maneesh author Mallya, Kavita author Batra, Surinder K author Jarnagin, William R author Schwartz, Robert E author Matei, Irina author Peinado, Héctor author Stanger, Ben Z author Bromberg, Jacqueline author Lyden, David author 2015-06 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. Nat Cell Biol . 2015;17(6):816-26 http://hdl.handle.net/20.500.12105/17975 25985394 10.1038/ncb3169 1476-4679 Nature cell biology http://hdl.handle.net/20.500.12105/17975 Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.