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, Professor 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, Professor 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| 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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