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    HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

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    Author
    Brunton, H; Caligiuri, G; Cunningham, R; Upstill-Goddard, R; Bailey, U-M; Garner, IM; Nourse, C; Dreyer, S; Jones, M; Moran-Jones, K; ...
    Date
    2020-05-12
    Source Title
    Cell Reports
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Grimmond, Sean; Brown, Robert
    Affiliation
    Melbourne Graduate School of Education
    Centre for Cancer Research
    Metadata
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    Document Type
    Journal Article
    Citations
    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. ,... 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 Status
    Open Access
    URI
    http://hdl.handle.net/11343/252406
    DOI
    10.1016/j.celrep.2020.107625
    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.

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