PT  - JOURNAL ARTICLE
AU  - Paola Martinelli
AU  - Enrique Carrillo-de Santa Pau
AU  - Trevor Cox
AU  - Bruno Sainz, Jr
AU  - Nelson Dusetti
AU  - William Greenhalf
AU  - Lorenzo Rinaldi
AU  - Eithne Costello
AU  - Paula Ghaneh
AU  - Núria Malats
AU  - Markus Büchler
AU  - Marina Pajic
AU  - Andrew V Biankin
AU  - Juan Iovanna
AU  - John Neoptolemos
AU  - Francisco X Real
TI  - GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer
AID  - 10.1136/gutjnl-2015-311256
DP  - 2017 Sep 01
TA  - Gut
PG  - 1665--1676
VI  - 66
IP  - 9
4099  - http://gut.bmj.com/content/66/9/1665.short
4100  - http://gut.bmj.com/content/66/9/1665.full
SO  - Gut2017 Sep 01; 66
AB  - Background and aims 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.Design 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.Results 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 GATA6low tumours 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.Conclusions 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.