title: BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.
abstract: The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rosati
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Basile
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: D'Auria
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: d'Avenia
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.
authors.forename: Margot
authors.initials: M
authors.lastname: De Marco
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Falco
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
authors.forename: Michelina
authors.initials: M
authors.lastname: Festa
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Guerriero
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Iorio
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Parente
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Pharmacy, Division of Biomedicine "A. Leone", University of Salerno, Fisciano, Salerno 84084, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pascale
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Liberato
authors.identifier: http://orcid.org/0000-0001-6133-4483
authors.initials: L
authors.lastname: Marzullo
authors.affiliation: Pathology Unit, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.affiliation: Animal facility, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.affiliation: Animal facility, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbieri
authors.affiliation: Animal facility, Istituto Nazionale Tumouri Fondazione "G. Pascale", Naples 81100, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Rea
authors.affiliation: Reconstructive Microsurgery, Department of Oncology, Careggi University Hospital, Florence 50139, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Menichini
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, Montpellier 34293, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam 1105AZ, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Bijlsma
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, Chieti 66100, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barcaroli
authors.affiliation: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, Chieti 66100, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sala
authors.affiliation: Division of Surgical Oncology, "S.S. Annunziata"Hospital, Chieti 66100, Italy.
authors.forename: Fabio Francesco
authors.initials: FF
authors.lastname: di Mola
authors.affiliation: Division of Surgical Oncology, "S.S. Annunziata"Hospital, Chieti 66100, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: di Sebastiano
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD, School of Medicine, San Diego, California 92093-0723, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD, School of Medicine, San Diego, California 92093-0723, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Antonucci
authors.affiliation: CALIXAR, Bioparc, Bâtiment Laënnec, Lyon 69008, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Corvest
authors.affiliation: CALIXAR, Bioparc, Bâtiment Laënnec, Lyon 69008, France.
authors.forename: Anass
authors.initials: A
authors.lastname: Jawhari
authors.affiliation: Department of Surgery, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
authors.forename: Matthew A
authors.identifier: http://orcid.org/0000-0002-7983-3982
authors.initials: MA
authors.lastname: Firpo
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Capunzo
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD, School of Medicine, San Diego, California 92093-0723, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, Chieti 66100, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: BIOUNIVERSA s.r.l., Fisciano, Salerno 84084, Italy.|Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Turco
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C498806:Bag3 protein, mouse; C080081:IFITM2 protein, human; D008565:Membrane Proteins; C479379:fragilis3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases