Tumour exosome integrins determine organotropic metastasis.

TitleTumour exosome integrins determine organotropic metastasis.
Publication TypeJournal Article
Year of Publication2015
AuthorsHoshino A, Costa-Silva B, Shen T-L, Rodrigues G, Hashimoto A, Mark MTesic, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez JM, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJørgen, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MSue, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg JF, Lyden D
Date Published2015 Nov 19
KeywordsAnimals, Biomarkers, Brain, Cell Line, Tumor, Endothelial Cells, Epithelial Cells, Exosomes, Female, Fibroblasts, Genes, src, Humans, Integrin alpha6beta1, Integrin alpha6beta4, Integrin beta Chains, Integrin beta4, Integrins, Kupffer Cells, Liver, Lung, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Organ Specificity, Phosphorylation, Receptors, Vitronectin, S100 Proteins, Tropism

Ever 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.

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Alternate JournalNature
PubMed ID26524530
PubMed Central IDPMC4788391
Grant ListR01-CA169416 / CA / NCI NIH HHS / United States
U01-CA169538 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
R01 CA169416 / CA / NCI NIH HHS / United States
R50 CA211462 / CA / NCI NIH HHS / United States

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