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

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-SilvaNicole M. AielloAllyson J. OceanSwarnima SinghHaiying ZhangBasant Kumar ThakurAnnette BeckerAyuko HoshinoMilica Tešić MarkHenrik MolinaJenny XiangTuo ZhangTill-Martin TheilenGuillermo García-SantosCaitlin WilliamsYonathan ArarsoYujie HuangGonçalo RodriguesTang-Long ShenKnut Jørgen LaboriInger Marie Bowitz LotheElin H. KureJonathan HernandezAlexandre DoussotSaya H. EbbesenPaul M. GrandgenettMichael A. HollingsworthManeesh JainKavita MallyaSurinder K. BatraWilliam R. JarnaginRobert E. SchwartzIrina MateiHéctor PeinadoBen Z. StangerJacqueline 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

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