Tumour exosome integrins determine organotropic metastasis.

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.

journal_name

Nature

journal_title

Nature

authors

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,Her

doi

10.1038/nature15756

subject

Has Abstract

pub_date

2015-11-19 00:00:00

pages

329-35

issue

7578

eissn

0028-0836

issn

1476-4687

pii

nature15756

journal_volume

527

pub_type

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