title: Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar-to-ductal metaplasia.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death. Through the process of acinar-to-ductal metaplasia (ADM), pancreatic acinar cells give rise to pancreatic intraepithelial neoplasia (PanIN), the most common precursor of PDA. However, even when Kras is activated in a majority of acinar cells, ADM and subsequent development of PanINs is inefficient in the absence of additional stresses. Numb regulates cell junctions, integrins, and the activity of embryonic signaling pathways; therefore, we investigated its effects on acinar cell dedifferentiation, regeneration, and metaplasia.
  
  
  METHODS
  We used mouse models of pancreatic regeneration and PDA as well as mice with loss-of-function alleles of Numb (p48Cre/p48Cre(ER);Numb(f/f) and p48Cre/p48Cre(ER);Kras(G12D);Numb(f/f) mice) to study the roles of Numb in pancreatic regeneration and ADM.
  
  
  RESULTS
  Loss of Numb resulted in premature dedifferentiation of acinar cells in response to injury due to administration of the cholecystokinin analogue cerulein and interfered with acinar cell regeneration. Numb was found to regulate multiple signaling pathways in acinar cells during cerulein-induced pancreatitis. Disruption of Numb accelerated and destabilized ADM in the context of oncogenic Kras (in p48Cre;Kras(G12D);Numb(f/f) and p48Cre(ER);Kras(G12D);Numb(f/f) mice).
  
  
  CONCLUSIONS
  Numb is an important regulator of acinar cell differentiation and viability during metaplasia. In mice with pancreatitis or pancreatic injury, elimination of Numb causes dedifferentiated acinar cells to undergo apoptosis, and this is not mitigated by oncogenic Kras.
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Greer
authors.forename: Binnaz K
authors.initials: BK
authors.lastname: Staley
authors.forename: Angela
authors.initials: A
authors.lastname: Liou
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D061354:Acinar Cells / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D054337:Cell Dedifferentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002108:Ceruletide / Q000009:adverse effects; D004195:Disease Models, Animal; D008565:Membrane Proteins / Q000502:physiology*; D008679:Metaplasia / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010179:Pancreas / Q000502:physiology; D010183:Pancreatic Ducts / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D016159:Tumor Suppressor Protein p53; D002108:Ceruletide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: 4′,6-diamidino-2-phenylindole; ADM; Acinar-to-Ductal Metaplasia; DAPI; FAK; Kras; PBS; PDA; PanIN; Pancreatitis; acinar-to-ductal metaplasia; focal adhesion kinase; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; phosphate-buffered saline
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