@article{5d57723d96db4a3e84de66ce779c3811,
title = "HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer",
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. 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.",
keywords = "chromatin landscapes, GATA6, GSK3B, HNF4A, intronic and distal promoters, metabolic targeting, PDAC subtypes, therapeutic tolerance",
author = "Holly Brunton and Giuseppina Caligiuri and Richard Cunningham and Rosie Upstill-Goddard and Ulla-Maja Bailey and Garner, {Ian M.} and Craig Nourse and Stephan Dreyer and Marc Jones and Kim Moran-Jones and Wright, {Derek W.} and Viola Paulus-Hock and Colin Nixon and Gemma Thomson and Jamieson, {Nigel B.} and McGregor, {Grant A.} and Lisa Evers and McKay, {Colin J.} and Aditi Gulati and Rachel Brough and Ilirjana Bajrami and Pettitt, {Stephen J.} and Dziubinski, {Michele L.} and Barry, {Simon T.} and Robert Gr{\"u}tzmann and Robert Brown and Edward Curry and {Glasgow Precision Oncology Laboratory} and {Australian Pancreatic Cancer Genome Initiative} and Sarah Allison and Cooke, {Susanna L.} and Paul Grimwood and Shane Kelly and Brian McDade and Daniel McElroy and Donna Ramsay and Selma Rebus and Jane Hair and Paul Westwood and Nicola Williams and Fraser Duthie and Johns, {Amber L.} and Amanda Mawson and Scarlett, {Christopher J.} and Brancato, {Mary Anne L.} and Rowe, {Sarah J.} and Simpson, {Skye H.} and Mona Martyn-Smith and Thomas, {Michelle T.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Angela Chou and Cowley, {Mark J.} and Humphris, {Jeremy L.} and Mead, {R. Scott} and Nagrial, {Adnan M.} and Jessica Pettit and Mark Pinese and Ilse Rooman and Jianmin Wu and Jiang Tao and Renee DiPietro and Clare Watson and Angela Steinmann and Lee, {Hong Ching} and Pinho, {Andreia V.} and Marc Giry-Laterriere and Daly, {Roger J.} and Sutherland, {Robert L.} and Grimmond, {Sean M.} and Nicola Waddell and Kassahn, {Karin S.} and Miller, {David K.} and Patch, {Ann Marie} and Sarah Song and Ivon Harliwong and Senel Idrisoglu and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Milena Gongora and Matthew Anderson and Oliver Holmes and Conrad Leonard and Darrin Taylor and Scott Wood and Christina Xu and Katia Nones and Fink, {J. Lynn} and Angelika Christ and Tim Bruxner and Nicole Cloonan and Felicity Newell and Pearson, {John V.} and Michael Quinn and Shivashankar Nagaraj and Stephen Kazakoff and Nick Waddell and Keerthana Krisnan and Kelly Quek and David Wood and Samra, {Jaswinder S.} and Gill, {Anthony J.} and Nick Pavlakis and Alex Guminski and Christopher Toon and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connnor and Lam, {Vincent W.} and Duncan McLeod and Pleass, {Henry C.} and Arthur Richardson and Virginia James and Kench, {James G.} and Cooper, {Caroline L.} and David Joseph and Charbel Sandroussi and Michael Crawford and James Gallagher and Michael Texler and Cindy Forest and Andrew Laycock and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Spry, {Nigel A.} and Bastiaan DeBoer and Ming Chai and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and Tan, {Chuan P.} and Tamara Debrencini and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Henry Tang and Barbour, {Andrew P.} and Clouston, {Andrew D.} and Patrick Martin and O'Rourke, {Thomas J.} and Amy Chiang and Fawcett, {Jonathan W.} and Kellee Slater and Shinn Yeung and Michael Hatzifotis and Peter Hodgkinson and Christopher Christophi and Mehrdad Nikfarjam and Angela Mountain and Eshleman, {James R.} and Hruban, {Ralph H.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Schulick, {Richard D.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Mary Hodgin and Aldo Scarpa and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Tempero, {Margaret A.} and Graham, {Janet S.} and Marina Pajic and Musgrove, {Elizabeth A.} and Petersen, {Gloria M.} and Emma Shanks and Alan Ashworth and Crawford, {Howard C.} and Simeone, {Diane M.} and Froeling, {Fieke E. M.} and Lord, {Christopher J.} and Debabrata Mukhopadhyay and Christian Pilarsky and Grimmond, {Sean E.} and Morton, {Jennifer P.} and Sansom, {Owen J.} and Chang, {David K.} and Bailey, {Peter J.} and Biankin, {Andrew V.}",
note = "Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
year = "2020",
month = may,
day = "12",
doi = "10.1016/j.celrep.2020.107625",
language = "English",
volume = "31",
pages = "1--17",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}