title: The conditional expression of KRAS G12D in mouse pancreas induces disorganization of endocrine islets prior the onset of ductal pre-cancerous lesions.
abstract: OBJECTIVE
  Pdx1-Cre; LSL-KRAS(G12D) mice develop premalignant pancreatic ductal lesions that can possibly progress spontaneously to pancreatic ductal adenocarcinoma (PDAC). Although Pdx1-Cre is expressed in the embryonic endoderm, which gives rise to all pancreatic lineages, the possible consequences of KRAS(G12D) expression in the endocrine compartment have never been finely explored.
  
  
  METHODS
  We examined by histology whether Pdx1-driven expression of KRAS(G12D) could induce islets of Langerhans defects.
  
  
  RESULTS
  We observed in Pdx1-Cre; LSL-KRAS(G12D) early disorganization of the endocrine compartment including i) hyperplasia affecting all the endocrine lineages, ii) ectopic onset of Ck19-positive (ductal-like) structures within the endocrine islets, and iii) the presence of islet cells co-expressing glucagon and insulin, all occurring before the onset of ducts lesions.
  
  
  CONCLUSIONS
  This work indicates that expression of KRAS(G12D) in Pdx1-expressing cells during embryogenesis affects the endocrine pancreas, and highlights the need to deepen possible consequences on both glucose metabolism and PDAC initiation.
authors.affiliation: TGFβ and Pancreatic Cancer Laboratory, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Gout
authors.forename: Roxane M
authors.initials: RM
authors.lastname: Pommier
authors.forename: David F
authors.initials: DF
authors.lastname: Vincent
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.forename: Sophie
authors.initials: S
authors.lastname: Goddard-Léon
authors.forename: Amélie
authors.initials: A
authors.lastname: Colombe
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Ulrich
authors.initials: U
authors.lastname: Valcourt
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000473:pathology*; D051379:Mice; D010179:Pancreas / Q000196:embryology / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis*; D015534:Trans-Activators / Q000096:biosynthesis
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D016283:Proto-Oncogene Proteins p21(ras)