HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.
HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.
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DOI：
10.1016/j.celrep.2020.107625
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发表时间：
2020-05-12
期刊：
影响因子：
8.8
通讯作者：
Biankin, Andrew, V
中科院分区：
文献类型：
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作者：
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.;Gruetzmann, 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
胰腺导管腺癌(PDAC)可分为转录转录亚型和两个广泛的谱系，称为经典(胰腺)和鳞状细胞癌。我们发现这两个亚型是由不同的代谢表型驱动的。失去了驱动内皮细胞谱系规范的基因HNF4a和GATA6，代谢谱从经典的(胰腺)转变为以鳞状为主，糖原合成酶激酶3β(GSK3β)是糖酵解的关键调节因子。GSK3b的药理抑制导致鳞状细胞亚型的选择性敏感性；然而，这些鳞状细胞患者来源的细胞系(PDCL)的一部分获得了快速的药物耐受。使用染色质可及性图，我们证明可以使用染色质可及性进一步分类鳞状细胞亚型，以预测对GSK3β抑制剂的反应性和耐受性。我们的发现表明，染色质可及性的不同模式可用于识别无法通过基因表达谱区分的患者亚组，突出了基于染色质的生物标记物在PDAC治疗中用于患者选择的实用价值。Brunton等人。证明不同染色质可及性可以预测鳞状细胞癌患者对GSK3β抑制剂的反应性和耐受性。这项研究提供了一个重要的概念证据，即染色质可及性可用于识别具有潜在治疗作用的其他PDAC亚群。
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 GSK3b 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.
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影响因子：
12.3
作者：
Boutros M;Brás LP;Huber W
通讯作者：
Huber W
影响因子：
24.5
作者：
Chou A;Froio D;Nagrial AM;Parkin A;Murphy KJ;Chin VT;Wohl D;Steinmann A;Stark R;Drury A;Walters SN;Vennin C;Burgess A;Pinese M;Chantrill LA;Cowley MJ;Molloy TJ;Australian Pancreatic Cancer Genome Initiative (APGI);Waddell N;Johns A;Grimmond SM;Chang DK;Biankin AV;Sansom OJ;Morton JP;Grey ST;Cox TR;Turchini J;Samra J;Clarke SJ;Timpson P;Gill AJ;Pajic M
通讯作者：
Pajic M
影响因子：
8.8
作者：
Candido JB;Morton JP;Bailey P;Campbell AD;Karim SA;Jamieson T;Lapienyte L;Gopinathan A;Clark W;McGhee EJ;Wang J;Escorcio-Correia M;Zollinger R;Roshani R;Drew L;Rishi L;Arkell R;Evans TRJ;Nixon C;Jodrell DI;Wilkinson RW;Biankin AV;Barry ST;Balkwill FR;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
30.8
作者：
Chan-Seng-Yue, Michelle;Kim, Jaeseung C.;Notta, Faiyaz
通讯作者：
Notta, Faiyaz
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J