title: The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice.
abstract: OBJECTIVE
  Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinar-ductal metaplasia, which is considered an initial step of mutant KRas-driven carcinogenesis. Therefore, the Gata6-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis.
  
  
  METHODS
  We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of KRas(G12V)-driven tumours
  
  
  RESULTS
  We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to KRas(G12V), thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of KRas(G12V)-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic Gata6-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR.
  
  
  CONCLUSIONS
  We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.
authors.affiliation: Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Paola
authors.initials: P
authors.lastname: Martinelli
authors.affiliation: Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Madriles
authors.affiliation: Comparative Pathology Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Enrique Carrillo-de Santa
authors.initials: EC
authors.lastname: Pau
authors.affiliation: Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Natalia Del
authors.initials: ND
authors.lastname: Pozo
authors.affiliation: Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.affiliation: Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C494760:Gata6 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CARCINOGENESIS; CELL BIOLOGY; DIFFERENTIATION; MOLECULAR MECHANISMS; PANCREATIC CANCER