HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
AuthorBrunton, H; Caligiuri, G; Cunningham, R; Upstill-Goddard, R; Bailey, U-M; Garner, IM; Nourse, C; Dreyer, S; Jones, M; Moran-Jones, K; ...
Source TitleCell Reports
AffiliationMelbourne Graduate School of Education
Centre for Cancer Research
Document TypeJournal Article
CitationsBrunton, 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. ,... Biankin, A. (2020). HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer. CELL REPORTS, 31 (6), https://doi.org/10.1016/j.celrep.2020.107625.
Access StatusOpen Access
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.
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