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GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer

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dc.contributor.author Martinelli, Paola
dc.contributor.author Carrillo, Enrique
dc.contributor.author Cox, Trevor
dc.contributor.author Sainz, Bruno Jr
dc.contributor.author Dusetti, Nelson
dc.contributor.author Greenhalf, William
dc.contributor.author Rinaldi, Lorenzo, 1986-
dc.contributor.author Costello, Eithne
dc.contributor.author Ghaneh, Paula
dc.contributor.author Malats i Riera, Núria
dc.contributor.author Büchler, Markus
dc.contributor.author Pajic, Marina
dc.contributor.author Biankin, Andrew V.
dc.contributor.author Iovanna, Juan
dc.contributor.author Neoptolemos, John
dc.contributor.author Real, Francisco X.
dc.date.accessioned 2018-03-08T09:18:04Z
dc.date.available 2018-03-08T09:18:04Z
dc.date.issued 2017
dc.identifier.citation Martinelli P, Carrillo-de Santa Pau E, Cox T, Sainz B Jr, Dusetti N, Greenhalf W et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017 Sep;66(9):1665-76. DOI: 10.1136/gutjnl-2015-311256
dc.identifier.issn 0017-5749
dc.identifier.uri http://hdl.handle.net/10230/34070
dc.description.abstract 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. 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/.
dc.description.sponsorship This work was supported, in part, by grants SAF2007-60860, SAF2011-29530 and ONCOBIO Consolider from Ministerio de Economía y Competitividad (Madrid, Spain), RTICC from Instituto de Salud Carlos III, grants 256974 and 289737 from European Union Seventh Framework Program to FXR and by grant P27361-B23 from the Austrian Science Fund (FWF) to PM. AB receives support from the Wellcome Trust, Cancer Research UK, the Medical Research Council (MRC), The Engineering and Physical Sciences Research Council (EPSRC), Pancreatic Cancer UK, the Chief Scientists Office (Scottish Government) and Pancreatic Cancer Action Network (USA). The Cancer Research UK Liverpool Clinical Trials Unit, the ESPAC trials, and the ESPAC tissue collections, storage and analyses are all funded by Cancer Research UK. PM was recipient of a Juan de la Cierva grant from Spanish Ministry of Science and Innovation. BSJr is recipient of a Ramón y Cajal Merit Award from the Spanish Ministry of Science and Innovation and a Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BMJ Publishing Group
dc.relation.ispartof Gut. 2017 Sep;66(9):1665-76
dc.rights © Martinelli P, et al. “This article was published in BMJ Open following peer review and can also be viewed on the journal’s website at http://bmjopen.bmj.com”. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1136/gutjnl-2015-311256
dc.subject.keyword Adjuvant treatment
dc.subject.keyword Cancer genetics
dc.subject.keyword Epithelial differentiation
dc.subject.keyword Gene regulation
dc.subject.keyword Pancreatic cancer
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/256974
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-60860
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29530
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/289737
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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