Brunton Holly, Caligiuri Giuseppina, Cunningham Richard, Upstill-Goddard Rosie, Bailey Ulla-Maja, Garner Ian M, Nourse Craig, Dreyer Stephan, Jones Marc, Moran-Jones Kim, Wright Derek W, Paulus-Hock Viola, Nixon Colin, Thomson Gemma, Jamieson Nigel B, McGregor Grant A, Evers Lisa, McKay Colin J, Gulati Aditi, Brough Rachel, Bajrami Ilirjana, Pettitt Stephen J, Dziubinski Michele L, Barry Simon T, Grützmann Robert, Brown Robert, Curry Edward, Pajic Marina, Musgrove Elizabeth A, Petersen Gloria M, Shanks Emma, Ashworth Alan, Crawford Howard C, Simeone Diane M, Froeling Fieke E M, Lord Christopher J, Mukhopadhyay Debabrata, Pilarsky Christian, Grimmond Sean E, Morton Jennifer P, Sansom Owen J, Chang David K, Bailey Peter J, Biankin Andrew V
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, Scotland; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, Scotland.
Cell Rep. 2020 May 12;31(6):107625. doi: 10.1016/j.celrep.2020.107625.
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.
胰腺导管腺癌（PDAC）可分为具有两种广泛谱系的转录组亚型，即经典型（胰腺型）和鳞状型。我们发现这两种亚型由不同的代谢表型驱动。驱动内胚层谱系特化的基因HNF4A和GATA6的缺失，会使代谢谱从经典型（胰腺型）转变为主要为鳞状型，糖原合酶激酶3β（GSK3β）是糖酵解的关键调节因子。对GSK3β的药理学抑制导致鳞状亚型具有选择性敏感性；然而，这些源自鳞状患者的细胞系（PDCLs）中的一部分会迅速获得药物耐受性。使用染色质可及性图谱，我们证明鳞状亚型可以根据染色质可及性进一步分类以预测对GSK3β抑制剂的反应性和耐受性。我们的研究结果表明，不同的染色质可及性模式可用于识别基因表达谱无法区分的患者亚组，突出了基于染色质的生物标志物在PDAC治疗中用于患者选择的实用性。
