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The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma

2014; Nature Portfolio; Volume: 16; Issue: 3 Linguagem: Inglês

10.1038/ncb2916

1476-4679

Guido von Figura, Akihisa Fukuda, Nilotpal Roy, Muluye E. Liku, John P. Morris, Grace Kim, Holger A. Russ, Matthew A. Firpo, Sean J. Mulvihill, David W. Dawson, Jorge Ferrer, William F. Mueller, Anke Busch, Klemens J. Hertel, Matthias Hebrok,

Neuroendocrine Tumor Research Advances

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets. Hebrok and colleagues use mouse models to demonstrate that loss of the chromatin modifier Brg1 cooperates with oncogenic KRas to form lesions resembling intraductal papillary mucinous neoplasia that progress to pancreatic adenocarcinoma.