Hoshino, AyukoCosta-Silva, BrunoShen, Tang-LongRodrigues, GoncaloHashimoto, AyakoTesic Mark, MilicaMolina, HenrikKohsaka, ShinjiDi Giannatale, AngelaCeder, SophiaSingh, SwarnimaWilliams, CaitlinSoplop, NadineUryu, KunihiroPharmer, LindsayKing, TariBojmar, LindaDavies, Alexander EArarso, YonathanZhang, TuoZhang, HaiyingHernandez, JonathanWeiss, Joshua MDumont-Cole, Vanessa DKramer, KimberlyWexler, Leonard HNarendran, AruSchwartz, Gary KHealey, John HSandstrom, PerLabori, Knut JørgenKure, Elin HGrandgenett, Paul MHollingsworth, Michael Ade Sousa, MariaKaur, SukhwinderJain, ManeeshMallya, KavitaBatra, Surinder KJarnagin, William RBrady, Mary SFodstad, OysteinMuller, VolkmarPantel, KlausMinn, Andy JBissell, Mina JGarcia, Benjamin AKang, YibinRajasekhar, Vinagolu KGhajar, Cyrus MMatei, IrinaPeinado, HectorBromberg, JacquelineLyden, David2024-02-122024-02-122015-11-19Nature . 2015 ;527(7578):329-35http://hdl.handle.net/20.500.12105/17970Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/TropismAnimalsBiomarkersBrainCell Line, TumorEndothelial CellsEpithelial CellsExosomesFemaleFibroblastsGenes, srcHumansIntegrin alpha6beta1Integrin alpha6beta4Integrin beta ChainsIntegrin beta4IntegrinsKupffer CellsLiverLungMiceMice, Inbred C57BLNeoplasm MetastasisOrgan SpecificityPhosphorylationReceptors, VitronectinS100 ProteinsAttribution-NonCommercial-NoDerivatives 4.0 Internacional26524530527757832910.1038/nature157561476-4687Naturehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788391/open access