HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosie Upstill-Goddard, Ulla-Maja Bailey, Ian M. Garner, Craig Nourse, Stephan Dreyer, Marc Jones, Kim Moran-Jones, Derek W. Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel Brough & 26 others Ilirjana Bajrami, Stephen J. Pettitt, Michele L. Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Glasgow Precision Oncology Laboratory, Australian Pancreatic Cancer Genome Initiative, Marina Pajic, Elizabeth A. Musgrove, Gloria M. Petersen, Emma Shanks, Alan Ashworth, Howard C. Crawford, Diane M. Simeone, Fieke E. M. Froeling, Christopher J. Lord, Debabrata Mukhopadhyay, Christian Pilarsky, Sean E. Grimmond, Jennifer P. Morton, Owen J. Sansom, David K. Chang, Peter J. Bailey*, Andrew V. Biankin

*Corresponding author for this work

Research output: Contribution to journalArticle

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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. Brunton et al. demonstrate that differential chromatin accessibility can predict responsiveness and tolerance to GSK3β inhibitors in the squamous subtype of PDAC. This study provides an important proof of concept that chromatin accessibility can be used to identify additional PDAC subgroups with potential therapeutic utility.

Original languageEnglish
Article number107625
Pages (from-to)1-17
Number of pages28
JournalCell Reports
Volume31
Issue number6
DOIs
Publication statusPublished - 12 May 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • chromatin landscapes
  • GATA6
  • GSK3B
  • HNF4A
  • intronic and distal promoters
  • metabolic targeting
  • PDAC subtypes
  • therapeutic tolerance

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    Brunton, H., Caligiuri, G., Cunningham, R., Upstill-Goddard, R., Bailey, U-M., Garner, I. M., ... Biankin, A. V. (2020). HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Reports, 31(6), 1-17. [107625]. https://doi.org/10.1016/j.celrep.2020.107625