title: MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice.
abstract: OBJECTIVE
  Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice.
  
  
  METHODS
  We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed.
  
  
  RESULTS
  PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1.
  
  
  CONCLUSIONS
  In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.
authors: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
authors: Meredith A
authors: MA
authors: Collins
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Wei
authors: W
authors: Yan
authors: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors: Judith S
authors: JS
authors: Sebolt-Leopold
authors: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan. Electronic address: marinapa@umich.edu.
authors: Marina
authors: M
authors: Pasca di Magliano
mesh_terms: D061354:Acinar Cells / Q000473:pathology* / Q000502:physiology; D000818:Animals; D002278:Carcinoma in Situ / Q000473:pathology / Q000503:physiopathology*; D054337:Cell Dedifferentiation / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D010195:Pancreatitis / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Acinar Differentiation; Mouse Models; Pancreatic Cancer; Signal Transduction