title: The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma.
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.
authors.affiliation: 1] 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].
authors.forename: Guido
authors.initials: G
authors.lastname: von Figura
authors.affiliation: 1] 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].
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2].
authors.forename: Nilotpal
authors.initials: N
authors.lastname: Roy
authors.affiliation: 1] Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA [2].
authors.forename: Muluye E
authors.initials: ME
authors.lastname: Liku
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Morris Iv
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA.
authors.forename: Holger A
authors.initials: HA
authors.lastname: Russ
authors.affiliation: 1] Department of Surgery [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.affiliation: 1] Department of Surgery [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulvihill
authors.affiliation: Department of Pathology, University of California, Los Angeles, California 90095, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Medicine, Imperial College London, W12 ONN London, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Mueller
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA.
authors.forename: Anke
authors.initials: A
authors.lastname: Busch
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA.
authors.forename: Klemens J
authors.initials: KJ
authors.lastname: Hertel
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)