BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

Alessandra Rosati, Anna Basile, Raffaella D’Auria, Morena d’Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Roberto Parente, Maria Pascale, Liberato Marzullo, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Maarten Bijlsma, Daniela Barcaroli, Gianluca Sala, Fabio Francesco di Mola, Pierluigi di Sebastiano, Jelena Todoric, Laura Antonucci, Vincent Corvest, Anass Jawhari, Matthew A Firpo, David A Tuveson, Mario Capunzo, Michael Karin, Vincenzo De Laurenzi () and Maria Caterina Turco ()
Additional contact information
Alessandra Rosati: BIOUNIVERSA s.r.l.
Anna Basile: BIOUNIVERSA s.r.l.
Raffaella D’Auria: BIOUNIVERSA s.r.l.
Morena d’Avenia: BIOUNIVERSA s.r.l.
Margot De Marco: BIOUNIVERSA s.r.l.
Antonia Falco: BIOUNIVERSA s.r.l.
Michelina Festa: BIOUNIVERSA s.r.l.
Luana Guerriero: BIOUNIVERSA s.r.l.
Vittoria Iorio: BIOUNIVERSA s.r.l.
Roberto Parente: BIOUNIVERSA s.r.l.
Maria Pascale: BIOUNIVERSA s.r.l.
Liberato Marzullo: BIOUNIVERSA s.r.l.
Renato Franco: Pathology Unit, Istituto Nazionale Tumouri Fondazione “G. Pascale”
Claudio Arra: Animal facility, Istituto Nazionale Tumouri Fondazione “G. Pascale”
Antonio Barbieri: Animal facility, Istituto Nazionale Tumouri Fondazione “G. Pascale”
Domenica Rea: Animal facility, Istituto Nazionale Tumouri Fondazione “G. Pascale”
Giulio Menichini: Reconstructive Microsurgery, Careggi University Hospital
Michael Hahne: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535
Maarten Bijlsma: Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam
Daniela Barcaroli: Orali e Biotecnologiche, University “G. d’Annunzio” di Chieti-Pescara, Centro Studi sull’Invecchiamento, CeSI-MeT
Gianluca Sala: Orali e Biotecnologiche, University “G. d’Annunzio” di Chieti-Pescara, Centro Studi sull’Invecchiamento, CeSI-MeT
Fabio Francesco di Mola: “S.S. Annunziata”Hospital
Pierluigi di Sebastiano: “S.S. Annunziata”Hospital
Jelena Todoric: Laboratory of Gene Regulation and Signal Transduction, UCSD, School of Medicine
Laura Antonucci: Laboratory of Gene Regulation and Signal Transduction, UCSD, School of Medicine
Vincent Corvest: CALIXAR, Bioparc, Bâtiment Laënnec
Anass Jawhari: CALIXAR, Bioparc, Bâtiment Laënnec
Matthew A Firpo: Huntsman Cancer Institute, University of Utah School of Medicine
David A Tuveson: Cold Spring Harbor Laboratory
Mario Capunzo: University of Salerno
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, UCSD, School of Medicine
Vincenzo De Laurenzi: BIOUNIVERSA s.r.l.
Maria Caterina Turco: BIOUNIVERSA s.r.l.

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9695

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