Tumour exosome integrins determine organotropic metastasis

Nature. 2015 Nov 19;527(7578):329-35. doi: 10.1038/nature15756. Epub 2015 Oct 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Brain / cytology
  • Brain / metabolism*
  • Cell Line, Tumor
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Exosomes / 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
  • Integrins / metabolism*
  • Kupffer Cells / cytology
  • Kupffer Cells / metabolism
  • Liver / cytology
  • Liver / metabolism*
  • Lung / cytology
  • Lung / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / pathology*
  • Neoplasm Metastasis / prevention & control*
  • Organ Specificity
  • Phosphorylation
  • Receptors, Vitronectin / antagonists & inhibitors
  • Receptors, Vitronectin / metabolism
  • S100 Proteins / genetics
  • Tropism*

Substances

  • Biomarkers
  • Integrin alpha6beta1
  • Integrin alpha6beta4
  • Integrin beta Chains
  • Integrin beta4
  • Integrins
  • Receptors, Vitronectin
  • S100 Proteins
  • integrin alphaVbeta5
  • integrin beta5

Associated data

  • GEO/GSE68919
  • figshare/10.6084/M9.FIGSHARE.1569781