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- Title
The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma.
- Authors
von Figura, Guido; Fukuda, Akihisa; Roy, Nilotpal; Liku, Muluye E.; Morris IV, John P.; Kim, Grace E.; Russ, Holger A.; Firpo, Matthew A.; Mulvihill, Sean J.; Dawson, David W.; Ferrer, Jorge; Mueller, William F.; Busch, Anke; Hertel, Klemens J.; Hebrok, Matthias
- Abstract
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.
- Subjects
PANCREATIC duct; DUCTAL carcinoma; CERVICAL intraepithelial neoplasia; PAPILLARY carcinoma; CHROMATIN; PANCREATIC acinar cells; TUMORS
- Publication
Nature Cell Biology, 2014, Vol 16, Issue 3, p255
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb2916