title: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
abstract: Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver 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 Medical College, New York, New York 10021, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Costa-Silva
authors.affiliation: Gastroenterology Division, Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Aiello
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Allyson J
authors.initials: AJ
authors.lastname: Ocean
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 Medical College, 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 Medical College, New York, New York 10021, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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 Medical College, New York, New York 10021, USA [2] Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Basant Kumar
authors.initials: BK
authors.lastname: Thakur
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 Medical College, New York, New York 10021, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Becker
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 Medical College, New York, New York 10021, USA.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Milica Tešić
authors.initials: MT
authors.lastname: 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: Genomics Resources Core Facility, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Genomics Resources Core Facility, Weill Cornell Medical College, 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 Medical College, New York, New York 10021, USA.
authors.forename: Till-Martin
authors.initials: TM
authors.lastname: Theilen
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 Medical College, New York, New York 10021, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Santos
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 Medical College, New York, New York 10021, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Williams
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 Medical College, New York, New York 10021, USA.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Ararso
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 Medical College, New York, New York 10021, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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 Medical College, New York, New York 10021, USA [2] Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Rodrigues
authors.affiliation: Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
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: 1] Department of Pathology, Oslo University Hospital, Nydalen, Oslo 0424, Norway [2] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
authors.forename: Inger Marie Bowitz
authors.initials: IM
authors.lastname: Lothe
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.affiliation: 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: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Doussot
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 Medical College, New York, New York 10021, USA.
authors.forename: Saya H
authors.initials: SH
authors.lastname: Ebbesen
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: 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.
authors.forename: Surinder K
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: Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schwartz
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 Medical College, New York, New York 10021, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Matei
authors.affiliation: 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 Medical College, New York, New York 10021, USA [2] Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Peinado
authors.affiliation: Gastroenterology Division, Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.affiliation: 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 Medical College, New York, New York 10021, USA [2] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lyden
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000473:pathology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011230:Precancerous Conditions / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005353:Fibronectins; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta