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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
The raw data for quantitative mass spectrometry analysis of lung-tropic (4173 and 4175), liver-tropic (HPAF-II and HCT116) and brain-tropic (831 and 231BR) exosomes (Fig. 2a and Extended Data Fig. 3a) are available at http://dx.doi.org/10.6084/m9.figshare.1569781. The raw sequencing data for human Kupffer cells treated in vitro with BxPC-3 or BxPC-3 ITGβ5KD exosomes have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE68919.
We thank S. Rudchenko at the Hospital for Special Surgery Flow Cytometry Core Facility. We acknowledge the MSK Cancer Center Support Grant/Core Grant (P30 CA008748). Our work is supported by grants from National Cancer Institute (U01-CA169538, D.L. and M.S.B.), National Institutes of Health (R01-CA169416, D.L. and H.P.), United States Department of Defense (W81XWH-13-10249, D.L.), W81XWH-13-1-0425 (D.L., J.B., B.A.G. and Y.K.), Melanoma Research Alliance (H.P.), Sohn Conference Foundation (H.P. and H.Z.), the Children’s Cancer and Blood Foundation (H.P. and D.L.), The Manning Foundation (D.L.), The Hartwell Foundation (D.L.), Fundação para a Ciência e a Técnologia (D.L.), The Nancy C. and Daniel P. Paduano Foundation (H.P. and D.L.), The Feldstein Foundation (H.P.), The Starr Cancer Consortium (H.P. and D.L.), The Mary Kay Foundation (D.L.), Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC, D.L. and H.P.), James Paduano Foundation (D.L. and H.P.), Beth Tortolani Foundation (D.L. and J.B.), Malcolm Hewitt Weiner Foundation (D.L.), Theodore A. Rapp Foundation (D.L.), American Hellenic Educational Progressive Association 5th District Cancer Research Foundation (D.L., A.H.), Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), Breast Cancer Alliance (J.B.), Manhasset Women’s Coalition Against Breast Cancer (J.B.), Ministry of Science and Technology Taiwan (101-2918-I-002-016, T.-L.S.), The JSPS Postdoctoral Fellowships for Research Abroad and Susan G. Komen Postdoctoral Fellowship (A.H.).
Extended data figures
This file contains western blot source data. a-h, Analysis of ITGβ4, α6, β1, α2, β3, αV, β5 and α3 expression, respectively, in organotropic cell line-derived exosomes in Fig. 2b. i-k, Analysis of ITGβ4, ITGα6 and GAPDH expression, respectively, in cell lysates versus exosomes derived from organotropic breast cancer and pancreatic cancer cell lines in Extended Fig. 3c. l, Analysis of ITGβ4 and GAPDH expression in 4175-LuT and 4175β4KD cells and exosomes in Extended Fig. 6a. m, Analysis of ITGβ4 and GAPDH expression in exosomes isolated from WT or ITGβ4-overexpressing1833-BoT cells in Extended Fig. 6c. n, Analysis of ITGβ5 and GAPDH expression in BxPC-3 and BxPC-3β5KD cells and exosomes in Extended Fig. 6e. o, Exosomal ITGβ4 and Alix levels in the plasma of mice bearing orthotopic 4175-Lu-T tumors in Extended Fig. 8a. LC, loading control.