Article Text
Abstract
Objective GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy.
Design We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.
Results GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. 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 GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
- pancreatic cancer
- molecular oncology
- cell biology
- epithelial differentiation
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request.
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Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request.
Footnotes
IF and SZ contributed equally.
Contributors MPdA and FXR, together with PM, designed the study, analysed the results and wrote the manuscript. MPdA performed the majority of the experiments; IF carried out the Cut&Run experiments and SZ performed the functional in vitro studies. The bioinformatics analyses were done by MPdA and JMdV. RJJ performed the statistical analysis with contributions from NM. CP, AMS, TK, PR and WW provided samples and clinical information. EC, WG, PG, DP, MB, TH, and JPN were involved in the ESPAC-3 trial and provided samples and clinical information. GHJ, SG and FN obtained data and analysed the associations with treatment response in the COMPASS trial. All authors provided comments to the manuscript. FXR supervised the overall conduct of the study, obtained funds and is the guarantor.
Funding The work was supported, in part, by the following grants: RTI2018-101071-B-I00 (Ministerio de Ciencia, Innovación y Universidades-MCIU, Madrid, Spain) to FXR, PI18/01347 (ISCIII-FIS, Madrid, Spain) to NM, PRECODE (EU-MSCA: 861196) to CP. (PanCuRx is supported by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, the Pancreatic Cancer Canada Foundation and a charitable donation from the Canadian Friends of the Hebrew University (Alex U Soyka). MPdA was supported by a PhD Fellowship from MCIU. SZ is recipient of a grant from the Marie Skłodowska-Curie Program of the European Commission (PDASwITch-895943). CNIO is supported by MCIU as a Centro de Excelencia Severo Ochoa (grant SEV-2015-0510).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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