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

Abstract

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.

A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models

“…GATA6 is a well-established master regulator of endoderm development and differentiation as well as pancreas organogenesis and homeostasis ( 48 – 53 ). In pancreatic tumors, GATA6 also promotes cancer cell differentiation and restricts cancer progression in part through maintaining features of the pancreatic lineage ( 60 – 63 ). Based on transcriptomic profiling, pancreatic tumors have been classified into 2 major subtypes: a classical subtype that consists of well/moderately differentiated tumors associated with better disease progression and patient survival; and a basal-like/squamous subtype that consists of poorly differentiated tumors with mesenchymal features and poorer outcome ( 7 , 64 – 67 ).…”

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

“…In particular, GATA6 has been demonstrated as a critical regulator of the classical programme and thus a valid surrogate biomarker of the classical subtype ( Martinelli et al, 2017 ; Aung et al, 2018 ). However, it has been recently shown that, while necessary, GATA6 loss is not sufficient to drive the basal phenotype ( Kloesch et al, 2021 ). Further downregulation of other endodermal fate determinants such HNF1A and HNF4A is also needed for the complete switch from classical to squamous/basal-like subtype ( Kloesch et al, 2021 ).…”

“…However, it has been recently shown that, while necessary, GATA6 loss is not sufficient to drive the basal phenotype ( Kloesch et al, 2021 ). Further downregulation of other endodermal fate determinants such HNF1A and HNF4A is also needed for the complete switch from classical to squamous/basal-like subtype ( Kloesch et al, 2021 ). This is supported further by the fact that HNF4A loss also causes a switch to a squamous metabolic profile in human PDAC cell lines ( Brunton et al, 2020 ).…”

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

“…The strategy to induce subtype switching in PDAC has been further explored based on the transcription factor GATA-binding factor 6 (GATA6) role as a regulator of classical PDAC subtype identity [28]. Depletion of GATA6 enforces a basal-like state in PDAC [95]. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is a transcriptional regulator of GATA6 in PDAC and blocking EZH2 reinstated GATA6 and induced gene signatures seen in the classical PDAC subtype, which confers a survival benefit [96].…”