Résumé
Interactions between cancer cells and stromal cells are critically involved in tumor formation, progression and development of metastasis. Here we report for the first time that human pancreatic adenocarcinoma (PDAC) cells secrete BAG3 that binds and activates macrophages, inducing their activation and the secretion of pancreatic cancer- supporting factors. We also identify IFITM-2 as a BAG3 receptor, by its co-precipitation with BAG3 from macrophage cell membrane and by impairment of BAG3- induced activation in IFITM-2- silenced macrophages. Finally we show the importance of this pathway in vivo since in nu/nu mice carrying orthotopic xenografts of human PDAC (MIA PaCa-2) cells, BAG3 sequestration by an anti-BAG3 antibody results in reduced tumor growth and prevents metastastasis formation. In conclusion we have identified a novel paracrine loop involved in PDAC growth and metastatic spreading and shown that its pharmacological blockage with an anti-BAG3 antibody has therapeutic potential. Citation Format: Alessandra Rosati, Anna Basile, Raffaella D'Auria, Morena d'Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Maria Pascale, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Marteen Bijlsma, Daniela Barcaroli, David A. Tuveson, Jelena Todoric, Michael Karin, Vincenzo De Laurenzi, Maria Caterina Turco. PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2393. doi:10.1158/1538-7445.AM2015-2393