HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Brunton, H. et al. (2020) HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Reports, 31(6), 107625. (doi: 10.1016/j.celrep.2020.107625) (PMID:32402285)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jamieson, Dr Nigel and Wright, Mr Derek and Dreyer, Dr Stephan and Bailey, Dr Peter and Shanks, Dr Emma and Evers, Ms Lisa and Bailey, Dr Ulla-Maja and Upstill-Goddard, Dr Rosie and Biankin, Professor Andrew and Musgrove, Dr Elizabeth and McGregor, Dr Grant and Moran-Jones, Dr Kim and Caligiuri, Giuseppina and Nixon, Mr Colin and Grimmond, Professor Sean and Morton, Professor Jen and Paulus-Hock, Mrs Viola and Thomson, Miss Gemma and McKay, Mr Colin and Brown, Prof Robert and Chang, Dr David and Jones, Mr Marc and Nourse, Dr Craig and Sansom, Professor Owen
Creator Roles:
Bailey, P. J.Conceptualization, Methodology, Software, Formal analysis, Writing – original draft, Writing – review and editing, Visualization
Caligiuri, G.Methodology, Investigation
Chang, D. K.Methodology, Funding acquisition
Jamieson, N. B.Methodology
McKay, C. J.Methodology
Musgrove, E. A.Methodology
Biankin, A. V.Methodology, Writing – review and editing, Funding acquisition
Dreyer, S.Methodology
Brown, R.Methodology
Grimmond, S. E.Methodology, Funding acquisition
Sansom, O. J.Methodology, Funding acquisition
Shanks, E.Investigation
McGregor, G. A.Investigation
Nixon, C.Investigation
Thomson, G.Investigation
Nourse, C.Investigation
Moran-Jones, K.Investigation
Jones, M.Investigation
Evers, L.Investigation
Morton, J. P.Investigation, Funding acquisition
Paulus-Hock, V.Investigation
Wright, D. W.Software
Upstill-Goddard, R.Software, Formal analysis
Authors: Brunton, H., Caligiuri, G., Cuunningham, R., Upstill-Goddard, R., Bailey, U.-M., Garner, I. M., Nourse, C., Dreyer, S., Jones, M., Moran-Jones, K., Wright, D. W., Paulus-Hock, V., Nixon, C., Thomson, G., Jamieson, N. B., McGregor, G. A., Evers, L., McKay, C. J., Gulati, A., Brough, R., Bajrami, I., Pettitt, S. J., Dziubinski, M. L., Barry, S. T., Grützmann, R., Brown, R., Curry, E., Pajic, M., Musgrove, E. A., Petersen, G. M., Shanks, E., Ashworth, A., Crawford, H. C., Simeone, D. M., Froeling, F. E.M., Lord, C. J., Mukhopadhyay, D., Pilarsky, C., Grimmond, S. E., Morton, J. P., Sansom, O. J., Chang, D. K., Bailey, P. J., and Biankin, A. V.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Cell Reports 31(6): 107625
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
169396Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CRUK)C29717/A17263Institute of Cancer Sciences
169638Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CRUK)C29717/A18484CS -Translational Research Centre
190874CR-UK Centre renewalKaren VousdenNot Applicable (NA)C596/A18076Institute of Cancer Sciences
172008Clinical Training Award Cycle 2Andrew BiankinCancer Research UK (CRUK)C596/A20921CS -Translational Research Centre
174160Precision PancAndrew BiankinCancer Research UK (CRUK)C29717/A23526CS -Translational Research Centre
170634Defining Platinum and PARP Responsive Molecular Phenotypes of Pancreatic Cancer.Andrew BiankinWellcome Trust (WELLCOTR)103721/Z/14/ZInstitute of Cancer Sciences
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research