BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

Alessandra Rosati, Anna Basile, Raffaella DAuria, Morena DAvenia, 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 BarcaroliGianluca 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, Maria Caterina Turco

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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.

Original languageEnglish
Article number8695
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Nov 2 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Rosati, A., Basile, A., DAuria, R., DAvenia, M., De Marco, M., Falco, A., Festa, M., Guerriero, L., Iorio, V., Parente, R., Pascale, M., Marzullo, L., Franco, R., Arra, C., Barbieri, A., Rea, D., Menichini, G., Hahne, M., Bijlsma, M., ... Turco, M. C. (2015). BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages. Nature Communications, 6, [8695]. https://doi.org/10.1038/ncomms9695