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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

1
Children'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.
2
Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan.
3
Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
4
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
5
Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
7
Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
8
Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA.
9
Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
10
Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.
11
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
12
Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA.
13
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
14
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
15
Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada.
16
Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA.
17
Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
18
Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
19
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
20
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
21
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
22
Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
23
Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
24
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway.
25
Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany.
26
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
27
Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
28
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
29
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
30
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
31
Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
32
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
33
Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
34
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
35
Department 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
PMCID:
PMC4788391
DOI:
10.1038/nature15756
[Indexed for MEDLINE]
Free PMC Article

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