GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer.
The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC.



We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy.



GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET2) transition. Patients with basal-like GATA6lowtumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU.



We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.
Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.|Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria.
Paola
P
Martinelli
Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
Enrique
E
Carrillo-de Santa Pau
Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK.|NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Trevor
T
Cox
Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain.
Bruno
B
Sainz
Centre 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.
Nelson
N
Dusetti
NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
William
W
Greenhalf
Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.|Institute for Research in Biomedicine (IRB), Barcelona, Spain.
Lorenzo
L
Rinaldi
Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK.
Eithne
E
Costello
Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK.|NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Paula
P
Ghaneh
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
Núria
N
Malats
Department for General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Markus
M
Büchler
Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
Marina
M
Pajic
Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.|South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia.
Andrew V
AV
Biankin
Centre 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.
Juan
J
Iovanna
Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK.|NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
John
J
Neoptolemos
Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain.|Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Francisco X
FX
Real
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D017024:Chemotherapy, Adjuvant / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D013223:Statistics as Topic
D000964:Antimetabolites, Antineoplastic; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D005472:Fluorouracil
ADJUVANT TREATMENT; CANCER GENETICS; EPITHELIAL DIFFERENTIATION; GENE REGULATION; PANCREATIC CANCER