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Nat Cell Biol. 2014 Mar;16(3):255-67. doi: 10.1038/ncb2916. Epub 2014 Feb 23.

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

Author information

  • 11] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany [3].
  • 21] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan [3].
  • 31] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2].
  • 4Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA.
  • 5Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA.
  • 61] Department of Surgery [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA.
  • 7Department of Pathology, University of California, Los Angeles, California 90095, USA.
  • 8Department of Medicine, Imperial College London, W12 ONN London, UK.
  • 9Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA.

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.

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PMID:
24561622
[PubMed - indexed for MEDLINE]
PMCID:
PMC4684081
Free PMC Article
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