title: Molecular mechanism of intraductal papillary mucinous neoplasm and intraductal papillary mucinous neoplasm-derived pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies. Dissecting the mechanisms underlying PDA development is important for developing early detection methods and effective prevention and therapies for the disease. PDA is considered to arise from distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, little is known about molecular mechanisms of development of IPMN and IPMN-derived PDA. We have recently reported that loss of Brg1, a core subunit of SWI/SNF chromatin remodeling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Brg1 null IPMN-PDA is less lethal compared to PanIN-derived PDA (PanIN-PDA) driven by mutant Kras and hemizygous p53 deletion, mirroring prognostic trends in PDA patients. Brg1 null IPMN-PDA possesses a distinct molecular signature that supports less malignant potential compared to PanIN-PDA. Furthermore, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, Brg1 is a determinant of context-dependent Kras-driven pancreatic tumorigenesis and chromatin remodeling may underlie the development of distinct PDA subsets. Understanding molecular mechanism of IPMN and IPMN-derived PDA could provide critical clues for novel diagnostic and therapeutic strategies of the disease.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Syougoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. fukuda26@kuhp.kyoto-u.ac.jp.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology*; D000231:Adenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
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)
keywords: Cellular origin; Chromatin remodeling; Intraductal papillary mucinous neoplasia; Mouse model; Pancreatic cancer