A GATA6-centred gene regulatory network involving HNFs and "np63 controls plasticity and immune escape in pancreatic cancer

Bernhard Kloesch, Vivien Ionasz, Sumit Paliwal, Natascha Hruschka, Jaime Martinez De Villarreal, Rupert Öllinger, Sebastian Mueller, Hans Peter Dienes, Martin Schindl, Elisabeth S. Gruber, Judith Stift, Dietmar Herndler-Brandstetter, Gwen A. Lomberk, Barbara Seidler, Dieter Saur, Roland Rad, Raul A. Urrutia, Francisco X. Real, Paola Martinelli

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Objective Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including "Np63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. Design We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRas G12D -driven pancreatic tumorigenesis (Gata6 LateKO). Results This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of "Np63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. Conclusions Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.

Original languageEnglish
Pages (from-to)766-777
Number of pages12
JournalGut
Volume71
Issue number4
DOIs
StatePublished - 1 Apr 2022

Keywords

  • epithelial differentiation
  • molecular mechanisms
  • pancreatic cancer

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