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BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.

  • Author(s): Rosati, Alessandra
  • Basile, Anna
  • D'Auria, Raffaella
  • d'Avenia, Morena
  • De Marco, Margot
  • Falco, Antonia
  • Festa, Michelina
  • Guerriero, Luana
  • Iorio, Vittoria
  • Parente, Roberto
  • Pascale, Maria
  • Marzullo, Liberato
  • Franco, Renato
  • Arra, Claudio
  • Barbieri, Antonio
  • Rea, Domenica
  • Menichini, Giulio
  • Hahne, Michael
  • Bijlsma, Maarten
  • Barcaroli, Daniela
  • Sala, Gianluca
  • di Mola, Fabio Francesco
  • di Sebastiano, Pierluigi
  • Todoric, Jelena
  • Antonucci, Laura
  • Corvest, Vincent
  • Jawhari, Anass
  • Firpo, Matthew A
  • Tuveson, David A
  • Capunzo, Mario
  • Karin, Michael
  • De Laurenzi, Vincenzo
  • Turco, Maria Caterina
  • et al.
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.

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