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

Tumour exosome integrins determine organotropic metastasis.

Author information

  • 1Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA.
  • 2Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan.
  • 3Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
  • 4Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
  • 5Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
  • 6Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 7Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
  • 8Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA.
  • 9Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
  • 10Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.
  • 11Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
  • 12Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA.
  • 13Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 14Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 15Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada.
  • 16Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA.
  • 17Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 18Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
  • 19Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
  • 20Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
  • 21Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
  • 22Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 23Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
  • 24Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway.
  • 25Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany.
  • 26Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
  • 27Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 28Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 29Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
  • 30Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
  • 31Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 32Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
  • 33Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
  • 34Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 35Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA.

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.

PMID:
26524530
[PubMed - indexed for MEDLINE]
PMCID:
PMC4788391
Free PMC Article
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