2014
DOI: 10.1038/ncb2916
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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 progres… Show more

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Cited by 170 publications
(197 citation statements)
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References 61 publications
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“…Brg1 acts as a tumor suppressor in the murine pancreas (von Figura et al, 2014). In addition, inactivating mutations in Brg1 and other subunits of SWI/SNF complexes have been identified in various human cancers, including the pancreas and intestine (Helming et al, 2014;Wilson and Roberts, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…Brg1 acts as a tumor suppressor in the murine pancreas (von Figura et al, 2014). In addition, inactivating mutations in Brg1 and other subunits of SWI/SNF complexes have been identified in various human cancers, including the pancreas and intestine (Helming et al, 2014;Wilson and Roberts, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…GEMMs of IPMN and, to a much lesser extent, MCN have also been generated using oncogenic Kras combined with either transforming growth factor α (Tgfα) overexpression, Smad4 deletion, Acvr1b loss, or Smarca4 deficiency (Bardeesy et al 2006b;Siveke et al 2007;von Figura et al 2014;Qiu et al 2016). Although most studies have reported the contribution of the acinar cells to PanINs and PDAC, the fact that oncogenic Kras and Tgfα lead to IPMN formation when driven by either the Pdx1 or Ptf1a promoter, but not the Ela1 promoter, raises a question of whether acinar cells can readily give rise to IPMN as well (Siveke et al 2007).…”
Section: Pancreatic Ductal Adenocarcinoma (Pdac) Pathogenesismentioning
confidence: 99%
“…Specifically, reconstituted SMARCA4 expression in SMARCA4-deficient human PDAC cells suppresses cell growth (Shain et al 2012), and a GEMM shows that cooperation with Smarca4 deletion and oncogenic Kras promotes IPMN development and PDAC progression with shortened overall survival compared with mice engineered with oncogenic Kras alone (von Figura et al 2014). Interestingly, Smarca4 loss leads to dedifferentiation of pancreatic ductal cells and formation of IPMNlike precursor lesions (Roy et al 2015).…”
Section: Pdac Epigeneticsmentioning
confidence: 99%
“…Using transgenic models, Dr Hebrok demonstrated that the epigenetic regulator Brg1 plays a role in specification of progenitor cells for distinct subsets of PDA. Elimination of Brg1 in duct cells promotes IPMn-PDA formation, but inhibits PanIN-PDA from acinar cells (von Figura et al, 2014).…”
Section: Stem Cells In Cancermentioning
confidence: 97%