GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer
- Paola Martinelli 1,2, Enrique Carrillo-de Santa Pau 1, Trevor Cox 3,4, Bruno Sainz 5, Nelson Dusetti 6, William Greenhalf 4, Lorenzo Rinaldi 1,7, Eithne Costello 3, Paula Ghaneh 3,4, Núria Malats 8, Markus Büchler 9, Marina Pajic 10, Andrew V Biankin 10,11,12,13, Juan Iovanna 6, John Neoptolemos 3,4, Francisco X Real 1,14
- Paola Martinelli 1,2, Enrique Carrillo-de Santa Pau 1, Trevor Cox 3,4
- 1Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
- 2Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria.
- 3Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK.
- 4NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
- 5Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain.
- 6Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
- 7Institute for Research in Biomedicine (IRB), Barcelona, Spain.
- 8Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
- 9Department for General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
- 10Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
- 11Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
- 12West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
- 13South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia.
- 14Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
- 0Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
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View abstract on PubMed
Summary
This summary is machine-generated.GATA6 suppresses pancreatic cancer progression by inhibiting epithelial-mesenchymal transition. Loss of GATA6 predicts poor patient survival and response to adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC).
Area Of Science
- Oncology
- Molecular Biology
- Cancer Genetics
Background
- The role of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is debated, with conflicting evidence regarding its oncogenic or tumor-suppressive functions.
- While GATA6 amplification is observed in some PDAC tumors, high expression correlates with better patient outcomes and well-differentiated tumors.
Purpose Of The Study
- To elucidate the precise function of GATA6 in pancreatic ductal adenocarcinoma (PDAC).
- To understand the molecular mechanisms underlying GATA6's role in PDAC progression and patient response to therapy.
Main Methods
- Combined GATA6 gene silencing and overexpression in PDAC cell lines.
- Utilized GATA6 Chromatin Immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) data.
- Validated findings in primary patient samples, including those from the ESPAC-3 clinical trial.
Main Results
- GATA6 inhibits epithelial-mesenchymal transition (EMT) in vitro and tumor cell dissemination in vivo, exhibiting pro-epithelial and anti-mesenchymal activity.
- Loss of GATA6 in PDAC is associated with altered differentiation, a basal-like phenotype, and shorter patient survival.
- Patients with GATA6-low tumors show a poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin therapy, although GATA6 modulation in cells did not directly affect 5-FU response.
Conclusions
- GATA6 possesses a tumor-suppressive function in PDAC by regulating epithelial differentiation.
- Loss of GATA6 expression serves as a prognostic marker for patient survival and a predictive marker for response to adjuvant therapy.
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