1. Tumour exosome integrins determine organotropic metastasis.
- Author
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Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, 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 J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, and Lyden D
- Subjects
- Animals, Biomarkers metabolism, Brain cytology, Cell Line, Tumor, Endothelial Cells cytology, Endothelial Cells metabolism, Epithelial Cells cytology, Epithelial Cells metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Genes, src, Humans, Integrin alpha6beta1 metabolism, Integrin alpha6beta4 antagonists & inhibitors, Integrin alpha6beta4 metabolism, Integrin beta Chains metabolism, Integrin beta4 metabolism, Integrins antagonists & inhibitors, Kupffer Cells cytology, Kupffer Cells metabolism, Liver cytology, Lung cytology, Mice, Mice, Inbred C57BL, Organ Specificity, Phosphorylation, Receptors, Vitronectin antagonists & inhibitors, Receptors, Vitronectin metabolism, S100 Proteins genetics, Brain metabolism, Exosomes metabolism, Integrins metabolism, Liver metabolism, Lung metabolism, Neoplasm Metastasis pathology, Neoplasm Metastasis prevention & control, Tropism
- Abstract
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.
- Published
- 2015
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