HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Holly Brunton,Emma Shanks,Stephan Dreyer,Sean M Grimmond,Andrew V Biankin,Nigel B Jamieson,Colin Nixon,Lisa Evers,Craig Nourse,Peter J Bailey,Debabrata Mukhopadhyay,David K Chang,Richard Cunningham,Grant A Mcgregor,Christian Pilarsky,Alan Ashworth,Ulla-Maja Bailey,Simon T Barry,Giuseppina Caligiuri,Rachel Brough,Christopher J Lord,Edward Curry,Marina Pajic,Robert Grützmann,Derek W Wright,Owen J Sansom,Elizabeth A Musgrove,Kim Moran-Jones,Ilirjana Bajrami,Jennifer P Morton,Howard C Crawford,Stephen J Pettitt,Gemma Thomson,Viola Paulus-Hock,Gloria M Petersen,Aditi Gulati,Diane M Simeone,Michele Dziubinski ,Colin Mckay ,Rosanna Upstill-Goddard ,Marc D Jones ,Ian Garner ,Robert E Brown ,Fieke E M Froeling

doi:10.1016/j.celrep.2020.107625

Abstract

SUMMARYPancreatic 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 GSK3b 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.

Highlights

The prognosis for patients suffering from pancreatic ductal adenocarcinoma (PDAC) is extremely poor, with less than 8% of patients surviving for more than 5 years after diagnosis
PDAC patient-derived cell lines (PDCLs) Recapitulate Metabolic Profiles Observed in PDAC Bulk Tumor Tissue We have previously demonstrated that transcriptional networks involved in energy source generation differ substantially between the classical and squamous subtypes (Bailey et al, 2016)
Comparative analysis of bulk tumor and PDCL transcriptomes demonstrated that PDCLs faithfully recapitulate the two broad PDAC transcriptomic subtypes observed in bulk tumor samples (Figures S1A and S2A; Table S1)

Summary

Introduction

The prognosis for patients suffering from pancreatic ductal adenocarcinoma (PDAC) is extremely poor, with less than 8% of patients surviving for more than 5 years after diagnosis. PDAC is defined by a complex and heterogeneous mutational landscape with a handful of highly recurrent mutations in welldescribed cancer genes and a plethora of low-frequency events associated with genes of often unknown function (Bailey et al, 2016; Biankin et al, 2012; Humphris et al, 2017; Waddell et al, 2015; Witkiewicz et al, 2015). Establishing which of these events drive tumor progression and/or survival has proved challenging. The squamous subtype is further typified by mutations in members of the COMPASS-like complex that regulate histone methylation, including KDM6A, MLL2, and MLL3 (Andricovich et al, 2018; Bailey et al, 2016)

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Discussion

Conclusion