Costa-Silva, BrunoAiello, Nicole MOcean, Allyson JSingh, SwarnimaZhang, HaiyingThakur, Basant KumarBecker, AnnetteHoshino, AyukoMark, Milica TešićMolina, HenrikXiang, JennyZhang, TuoTheilen, Till-MartinGarcía-Santos, GuillermoWilliams, CaitlinArarso, YonathanHuang, YujieRodrigues, GonçaloShen, Tang-LongLabori, Knut JørgenLothe, Inger Marie BowitzKure, Elin HHernandez, JonathanDoussot, AlexandreEbbesen, Saya HGrandgenett, Paul MHollingsworth, Michael AJain, ManeeshMallya, KavitaBatra, Surinder KJarnagin, William RSchwartz, Robert EMatei, IrinaPeinado, HéctorStanger, Ben ZBromberg, JacquelineLyden, David2024-02-122024-02-122015-06Nat Cell Biol . 2015;17(6):816-26http://hdl.handle.net/20.500.12105/17975Pancreatic 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AnimalsBase SequenceBone Marrow CellsCarcinoma, Pancreatic DuctalCell Line, TumorCell MovementExosomesFemaleFibronectinsGene Expression Regulation, NeoplasticHepatic Stellate CellsHumansLiverLiver NeoplasmsMacrophage Migration-Inhibitory FactorsMacrophagesMiceMice, Inbred C57BLMice, KnockoutPancreatic NeoplasmsPrecancerous ConditionsRNA InterferenceRNA, Small InterferingSequence Analysis, RNASignal TransductionTransforming Growth Factor betaAttribution-NonCommercial-NoDerivatives 4.0 Internacional2598539417681610.1038/ncb31691476-4679Nature cell biologyhttp://hdl.handle.net/20.500.12105/17975open access