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Original research
GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma
  1. Mónica P de Andrés1,
  2. Richard J Jackson2,
  3. Irene Felipe1,3,
  4. Sladjana Zagorac1,
  5. Christian Pilarsky4,
  6. Anna Melissa Schlitter5,6,
  7. Jaime Martinez de Villareal1,3,
  8. Gun Ho Jang7,
  9. Eithne Costello8,
  10. Steve Gallinger7,9,10,11,12,
  11. Paula Ghaneh8,
  12. William Greenhalf8,
  13. Thomas Knösel13,
  14. Daniel H Palmer8,
  15. Petra Ruemmele14,
  16. Wilko Weichert5,
  17. Markus Buechler15,
  18. Thilo Hackert15,
  19. John P Neoptolemos15,
  20. Faiyaz Notta7,16,17,
  21. Núria Malats3,18,
  22. Paola Martinelli19,
  23. Francisco X Real20
  1. 1Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
  2. 2Institute of Translational Medicine, University of Liverpool, Liverpool, UK
  3. 3CIBERONC, Madrid, Spain
  4. 4Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany
  5. 5Institute of Pathology, School of Medicine, Technische Universitat Munchen, Munchen, Germany
  6. 6German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  7. 7PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  8. 8Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
  9. 9Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  10. 10Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University, Toronto, Ontario, Canada
  11. 11Health Network, Toronto, Ontario, Canada
  12. 12Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada
  13. 13Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
  14. 14Pathologisches Institute, Erlangen University Hospital, Erlangen, Germany
  15. 15Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
  16. 16Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  17. 17Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  18. 18Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
  19. 19Institute of Cancer Research, Clinic for Internal Medicine I, Medical University of Vienna, Vienna, Austria
  20. 20Departament de Medicina i Ciències de la Vida, Universitt Pompeu Fabra, Barcelona, Spain
  1. Correspondence to Dr Francisco X Real, Spanish National Cancer Research Centre, Madrid 28029, Spain; freal{at}cnio.es

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.

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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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.