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HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
Holly Brunton1, Giuseppina Caligiuri2, Richard Cunningham2
1Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, Scotland; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.
Insights
Pancreatic cancer subtypes have distinct metabolic profiles. Targeting glycogen synthase kinase 3 beta (GSK3β) shows promise, with chromatin accessibility predicting patient response and tolerance to treatment.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits transcriptomic heterogeneity, broadly classified into classical and squamous subtypes.
- These subtypes are characterized by distinct metabolic phenotypes, influencing therapeutic strategies.
Purpose of the Study:
- To investigate the metabolic drivers differentiating PDAC subtypes.
- To explore the efficacy and resistance mechanisms of glycogen synthase kinase 3 beta (GSK3β) inhibition in PDAC.
- To identify novel biomarkers for predicting treatment response.
Main Methods:
- Analysis of transcriptomic and metabolic profiles of PDAC subtypes.
- Pharmacological inhibition of GSK3β in patient-derived cell lines.
- Chromatin accessibility profiling to identify predictive biomarkers.
Main Results:
- Loss of HNF4A and GATA6 promotes a metabolic switch towards the squamous subtype, regulated by GSK3β.
- GSK3β inhibition selectively affects the squamous subtype, but drug tolerance emerges in a subset of cell lines.
- Chromatin accessibility patterns distinguish squamous PDAC subgroups, predicting responsiveness and tolerance to GSK3β inhibitors.
Conclusions:
- Distinct metabolic phenotypes underlie PDAC subtypes, offering therapeutic targets.
- GSK3β is a key regulator of glycolysis in squamous PDAC.
- Chromatin accessibility serves as a valuable biomarker for stratifying PDAC patients for targeted therapy.
