Journal
GUT
Volume 66, Issue 9, Pages 1665-1676Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2015-311256
Keywords
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Categories
Funding
- Ministerio de Economia y Competitividad (Madrid, Spain) [SAF2007-60860, SAF2011-29530]
- Instituto de Salud Carlos III
- European Union [256974, 289737]
- Austrian Science Fund (FWF) [P27361-B23]
- Wellcome Trust
- Cancer Research UK
- Medical Research Council (MRC)
- Engineering and Physical Sciences Research Council (EPSRC)
- Pancreatic Cancer UK
- Chief Scientists Office (Scottish Government)
- Pancreatic Cancer Action Network (USA)
- Spanish Ministry of Science and Innovation
- Ramon y Cajal Merit Award from the Spanish Ministry of Science and Innovation
- Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY
- MRC [MC_PC_15080, MR/N005813/1] Funding Source: UKRI
- Austrian Science Fund (FWF) [P27361] Funding Source: Austrian Science Fund (FWF)
- Cancer Research UK [16812, 15957, 17263, 11883, 17680, 8968, 16186] Funding Source: researchfish
- Chief Scientist Office [SGP/1] Funding Source: researchfish
- Medical Research Council [MR/N005813/1, MC_PC_15080] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10126, PB-PG-0407-13363, 08/29/02] Funding Source: researchfish
- Pancreatic Cancer UK [FLF2015_04_Glasgow] Funding Source: researchfish
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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 GATA6(low) 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.
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