Tumour exosome integrins determine organotropic metastasis

Ever since Stephen Pagets 1889 hypothesis, metastatic organotropism has remained one of cancers 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 alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) 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.
Funding Agencies|MSK Cancer Center Support Grant/Core Grant [P30 CA008748]; National Cancer Institute [U01-CA169538]; National Institutes of Health [R01-CA169416]; United States Department of Defense [W81XWH-13-10249, W81XWH-13-1-0425]; Melanoma Research Alliance; Sohn Conference Foundation; Childrens Cancer and Blood Foundation; Manning Foundation; Hartwell Foundation; Fundacao para a Ciencia e a Tecnologia; Nancy C. and Daniel P. Paduano Foundation; Feldstein Foundation; Starr Cancer Consortium; Mary Kay Foundation; Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC); James Paduano Foundation; Beth Tortolani Foundation; Malcolm Hewitt Weiner Foundation; Theodore A. Rapp Foundation; American Hellenic Educational Progressive Association 5th District Cancer Research Foundation; Charles and Marjorie Holloway Foundation; Sussman Family Fund; Lerner Foundation; Breast Cancer Alliance; Manhasset Womens Coalition Against Breast Cancer; Ministry of Science and Technology Taiwan [101-2918-I-002-016]; JSPS Postdoctoral Fellowships; Susan G. Komen Postdoctoral Fellowship