Afficher la couverture 'GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer | Martinelli, Paola' en grand format
/5

0 avis

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

Archive ouverte

Martinelli, Paola | Carrillo-de Santa Pau, Enrique | Cox, Trevor | Sainz Jr, Bruno | Dusetti, Nelson | Greenhalf, William | Rinaldi, Lorenzo | Costello, Eithne | Ghaneh, Paula | Malats, Núria | Büchler, Markus | Pajic, Marina | Biankin, Andrew | Iovanna, Juan, L. | Neoptolemos, John | Real, Francisco, X.

Edité par CCSD ; BMJ Publishing Group -

International audience. 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.

Suggestions

Du même auteur

Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma. Modèles de récidive après résection d'un adénocarcinome canalaire pancréatique. Analyse secondaire de l'essai randomisé de chimiothérapie adjuvante ESPAC-4

Archive ouverte | Jones, Robert P. | CCSD

International audience. Les schémas de récidive de la maladie après résection d’un adénocarcinome canalaire pancréatique avec chimiothérapie adjuvante restent flous.Objectif : définir les schémas de récidive après ...

Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials)

Archive ouverte | Bonnetain, Franck | CCSD

International audience. BACKGROUND:Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials...

NOTCH pathway inactivation promotes bladder cancer progression

Archive ouverte | Maraver, Antonio | CCSD

International audience. NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers r...

Chargement des enrichissements...