title: 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.
authors.affiliation: 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.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Costa-Silva
authors.affiliation: 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.|Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.affiliation: 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.|Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
authors.forename: Goncalo
authors.initials: G
authors.lastname: Rodrigues
authors.affiliation: 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.|Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Milica
authors.initials: M
authors.lastname: Tesic Mark
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Giannatale
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ceder
authors.affiliation: 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.
authors.forename: Swarnima
authors.initials: S
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Williams
authors.affiliation: Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Soplop
authors.affiliation: Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA.
authors.forename: Kunihiro
authors.initials: K
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authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Pharmer
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
authors.forename: Tari
authors.initials: T
authors.lastname: King
authors.affiliation: 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.|Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Bojmar
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Davies
authors.affiliation: 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.
authors.forename: Yonathan
authors.initials: Y
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authors.affiliation: Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.|Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: 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.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: Dumont-Cole
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Leonard H
authors.initials: LH
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authors.affiliation: Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada.
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.affiliation: Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA.
authors.forename: Gary K
authors.initials: GK
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authors.affiliation: Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.affiliation: Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Sandstrom
authors.affiliation: Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
authors.forename: Knut Jørgen
authors.initials: KJ
authors.lastname: Labori
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grandgenett
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: 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.|Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: de Sousa
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Sukhwinder
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Mallya
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
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authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jarnagin
authors.affiliation: 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.|Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Brady
authors.affiliation: Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway.|Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway.
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.affiliation: Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
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authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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authors.affiliation: Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
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authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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authors.initials: BA
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authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
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authors.affiliation: 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.
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authors.affiliation: 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.|Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Hector
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authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.affiliation: 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.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: David
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mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016391:Genes, src; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism; D039161:Integrin alpha6beta4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D039663:Integrin beta4 / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000517:prevention & control*; D009928:Organ Specificity; D010766:Phosphorylation; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics; D018523:Tropism
chemical_list: D015415:Biomarkers; D039121:Integrin alpha6beta1; D039161:Integrin alpha6beta4; D039641:Integrin beta Chains; D039663:Integrin beta4; D016023:Integrins; D019030:Receptors, Vitronectin; D009418:S100 Proteins; C064660:integrin alphaVbeta5; C084344:integrin beta5