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HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer


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 (GSK3beta) a key regulator of glycolysis. Pharmacological inhibition of GSK3beta 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 GSK3beta 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.

Type Journal
ISBN 2211-1247 (Electronic)
Authors Brunton, H.; Caligiuri, G.; Cunningham, 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.; Grutzmann, R.; Brown, R.; Curry, E.; Glasgow Precision Oncology, Laboratory; Australian Pancreatic Cancer Genome, Initiative; 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.; Biankin, A. V.
Responsible Garvan Author A/Prof Marina Pajic
Publisher Name Cell Reports
Published Date 2020-05-31
Published Volume 31
Published Issue 6
Published Pages 107625
Status Published in-print
DOI 10.1016/j.celrep.2020.107625
URL link to publisher's version
OpenAccess link to author's accepted manuscript version