Paola Martinelli1, Francesc Madriles1, Marta Cañamero2, Enrique Carrillo-de Santa Pau1, Natalia Del Pozo1, Carmen Guerra3, Francisco X Real4. 1. Epithelial Carcinogenesis Group, BBVA Foundation-Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. 2. Comparative Pathology Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. 3. Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. 4. 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.
Abstract
BACKGROUND AND AIMS: 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. DESIGN: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND AND AIMS: 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. DESIGN: We analysed genetically engineered mouse models and humanpancreatic 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
CARCINOGENESIS; CELL BIOLOGY; DIFFERENTIATION; MOLECULAR MECHANISMS; PANCREATIC CANCER
Authors: Paola Ulivi; Luca Saragoni; Chiara Molinari; Gianluca Tedaldi; Francesca Rebuzzi; Paolo Morgagni; Laura Capelli; Sara Ravaioli; Maria Maddalena Tumedei; Emanuela Scarpi; Anna Tomezzoli; Riccardo Bernasconi; Maria Raffaella Ambrosio; Alessia D'Ignazio; Leonardo Solaini; Francesco Limarzi; Giorgio Ercolani; Giovanni Martinelli Journal: Gastric Cancer Date: 2020-11-06 Impact factor: 7.370