Journal Article

A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

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

2022

Overview

ObjectiveMolecular 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 ΔNp63 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.DesignWe 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 KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO).ResultsThis comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of ΔNp63 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.ConclusionsOur 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Animals / Cancer / Carcinoma, Pancreatic Ductal - pathology / Classification / Classification systems / Datasets / Epigenetics / epithelial differentiation / GATA6 Transcription Factor - genetics / GATA6 Transcription Factor - metabolism / Gene expression / Gene Expression Regulation, Neoplastic / Gene Regulatory Networks / Genetic engineering / Genotype & phenotype / Hepatocyte nuclear factor 4 / Humans / Immune evasion / Lung cancer / Medical prognosis / Metastases / Metastasis / Mice / molecular mechanisms / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - pathology / Patients / Phenotypes / Plasticity / Precision medicine / Proteins / Recombinase / Therapeutic applications / Transcription factors / Transcriptomics / Tumorigenesis / Tumors