The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2014-03-01
Date Acceptance
2014-01-10
Citation
Nature Cell Biology, 2014, 16 (3), pp.255-267
ISSN
1476-4679
Publisher
Nature Publishing Group
Start Page
255
End Page
267
Journal / Book Title
Nature Cell Biology
Volume
16
Issue
3
Copyright Statement
Copyright © 2014, Rights Managed by Nature Publishing Group
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
CELL BIOLOGY
INTRAEPITHELIAL NEOPLASIA
INVASIVE ADENOCARCINOMA
TUMOR-SUPPRESSOR
CANCER
MUTATIONS
PROGRESSION
KRAS
EXPRESSION
CARCINOMA
CELLS
Publication Status
Published