GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Abstract

Objective: GATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome. Design:We analyzed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.Results: Subtype classification using transcriptomic data revealed that GATA4 mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 did not have a major transcriptional impact. However, concomitant low expression of GATA4 enhanced the transcriptomic effects of GATA6 low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. Conclusions:Our analyses uncover a cooperative interaction between GATA4 and GATA6 to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis.

The Relationship between the Expression of GATA4 and GATA6 with the Clinical Characteristics and Prognosis of Resectable Pancreatic Adenocarcinoma

“…However, other authors have described that GATA4 inhibits the proliferation of PDAC tumor cells and favors cell differentiation [24]. It has recently been reported that, in the basal-like subtype, the expression of GATA4 is downregulated and that the low expression of GATA4 amplifies the transcriptomic effect of GATA6 loss [25].…”

“…Also, GATA6 deletion in mice has been reported to dramatically increase the metastatic rate [28]. Furthermore, it should be noted that the loss of simultaneous expression of GATA4 and GATA6 has been reported to be related to the development of liver metastases [25].…”

Expression profile and prognostic values of GATA family members in kidney renal clear cell carcinoma

“…Grainne et al found that GATA6 regulates epithelial-mesenchymal transition and tumor dissemination and is a marker of adjuvant chemotherapy response in pancreatic ductal adenocarcinoma (PDAC) [ 31 , 32 ]. Moreover, Andrés et al demonstrated that GATA4 is a potential marker of tumor growth in PDAC and that the expression of GATA4 and GATA6 is a biomarker of poor prognosis and therapeutic response [ 33 ]. The clinical association and prognostic significance of abnormally expressed GATAs in patients with KIRC were then investigated.…”

BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states

“…Cut&Run genomic binding analysis. Cut&Run experiments were performed as described in 55 and 56 . Briefly, 500,000 cells/sample were harvested, bound to concanavalin A-coated magnetic beads, and permeabilized with 5% digitonin.…”