Details

Autor(en) / Beteiligte

• Brunton, Holly
• Caligiuri, Giuseppina
• Cunningham, Richard
• Upstill-Goddard, Rosie
• Garner, Ian M.
• Nourse, Craig
• Wright, Derek W.
• Nixon, Colin
• Jamieson, Nigel B.
• McGregor, Grant A.
• Evers, Lisa
• McKay, Colin J.
• Gulati, Aditi
• Brough, Rachel
• Pettitt, Stephen J.
• Dziubinski, Michele L.
• Grützmann, Robert
• Curry, Edward
• Allison, Sarah
• Biankin, Andrew V.
• Dreyer, Stephan
• McDade, Brian
• McElroy, Daniel
• Ramsay, Donna
• Westwood, Paul
• Mawson, Amanda
• Scarlett, Christopher J.
• Brancato, Mary-Anne L.
• Simpson, Skye H.
• Thomas, Michelle T.
• Chin, Venessa T.
• Humphris, Jeremy L.
• Mead, R. Scott
• Nagrial, Adnan M.
• Pettit, Jessica
• Wu, Jianmin
• DiPietro, Renee
• Steinmann, Angela
• Pinho, Andreia V.
• Giry-Laterriere, Marc
• Musgrove, Elizabeth A.
• Miller, David K.
• Song, Sarah
• Nourbakhsh, Ehsan
• Wani, Shivangi
• Gongora, Milena
• Anderson, Matthew
• Holmes, Oliver
• Leonard, Conrad
• Wood, Scott
• Bruxner, Tim
• Pearson, John V.
• Nagaraj, Shivashankar
• Kazakoff, Stephen
• Waddell, Nick
• Quek, Kelly
• Pavlakis, Nick
• Asghari, Ray
• Pavey, Darren
• Das, Amitabha
• Ismail, Kasim
• Lam, Vincent W.
• Richardson, Arthur
• James, Virginia
• Kench, James G.
• Joseph, David
• Laycock, Andrew
• Epari, Krishna P.
• Fletcher, David R.
• Zeps, Nikolajs
• Beilin, Maria
• Feeney, Kynan
• Worthley, Chris
• Tan, Chuan P.
• Debrencini, Tamara
• Chen, John
• Brooke-Smith, Mark E.
• Tang, Henry
• Clouston, Andrew D.
• Fawcett, Jonathan W.
• Slater, Kellee
• Hatzifotis, Michael
• Nikfarjam, Mehrdad
• Eshleman, James R.
• Hruban, Ralph H.
• Schulick, Richard D.
• Scarpa, Aldo
• Scardoni, Maria
• Tempero, Margaret A.
• Pajic, Marina
• Petersen, Gloria M.
• Shanks, Emma
• Pilarsky, Christian
• Grimmond, Sean E.
• Morton, Jennifer P.
• Chang, David K.
• Bailey, Peter J.

Titel

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Ist Teil von

• Cell reports (Cambridge), 2020-05, Vol.31 (6), p.107625-107625, Article 107625

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •HNF4A loss upregulates GSK3β and drives a squamous-like metabolic profile•GSK3β targeting inhibits glycolysis in squamous patient-derived cell lines (PDCLs)•A subset of squamous PDCLs acquires GSK3β drug tolerance•ATAC-seq analysis reveals an accessible WNT gene program in drug-tolerant PDCLs 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.