HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
Holly Brunton(Cancer Research UK), Giuseppina Caligiuri(University of Glasgow), Richard Cunningham(University of Glasgow), Rosanna Upstill‐Goddard(University of Glasgow), Ulla‐Maja Bailey(Cancer Research UK), Ian Garner(Imperial College London), Craig Nourse(Cancer Research UK), Stephan B. Dreyer(Glasgow Royal Infirmary), Marc D. Jones(Queen Elizabeth University Hospital), Kim Moran‐Jones(Queen Elizabeth University Hospital), Derek Wright(MRC University of Glasgow Centre for Virus Research), Viola Paulus-Hock(Cancer Research UK), Colin Nixon(Cancer Research UK), Gemma Thomson(Cancer Research UK), Nigel B. Jamieson(Glasgow Royal Infirmary), Grant A. McGregor(Cancer Research UK), Lisa Evers(University of Glasgow), Colin J. McKay(Glasgow Royal Infirmary), Aditi Gulati(Institute of Cancer Research), Rachel Brough(Institute of Cancer Research), Ilirjana Bajrami(Institute of Cancer Research), Stephen J. Pettitt(Institute of Cancer Research), Michele Dziubinski(University of Michigan), Simon T. Barry(AstraZeneca (United Kingdom)), Robert Grützmann(Universitätsklinikum Erlangen), Robert Brown(Imperial College London), Edward Curry(Imperial College London), Sarah Allison(Garvan Institute of Medical Research), Andrew V. Biankin(University of Glasgow), David K. Chang(Mayo Clinic in Arizona), Susanna L. Cooke(Cancer Research UK), Stephan B. Dreyer(Institute of Cancer Research), Paul Grimwood(University of Michigan), Shane Kelly(NYU Langone Health), John L. Marshall(Cold Spring Harbor Laboratory), Brian McDade(Institute of Cancer Research), Daniel L. McElroy(Jacksonville College), Donna Ramsay(Universitätsklinikum Erlangen), Rosanna Upstill‐Goddard(The University of Melbourne), Selma Rebus(Cancer Research UK), Jane Hair(Cancer Research UK), Nigel B. Jamieson(Glasgow Royal Infirmary), Colin J. McKay(Heidelberg University), Paul Westwood(Glasgow Royal Infirmary), Nicola Williams, Fraser R. Duthie(Glasgow Royal Infirmary), Andrew V. Biankin(Glasgow Royal Infirmary), Amber L. Johns, Amanda Mawson(Cancer Research UK), David K. Chang(University of Glasgow), Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith(University of Glasgow), Michelle T. Thomas, Lorraine A. Chantrill, Venessa Chin(Glasgow Royal Infirmary), Angela Chou(Glasgow Royal Infirmary), Mark J. Cowley(Cancer Research UK), Jeremy L. Humphris, R. Scott Mead, Adnan Nagrial(Glasgow Royal Infirmary), Marina Pajic(Garvan Institute of Medical Research), Jessica Pettit, Mark Pinese(Glasgow Royal Infirmary), Ilse Rooman(Institute of Cancer Research), Jianmin Wu, Tao Jiang, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterrière, Roger J. Daly, Elizabeth A. Musgrove(University of Glasgow), Robert L. Sutherland, Sean M. Grimmond(Garvan Institute of Medical Research), Nicola Waddell(Institute of Cancer Research), Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning(Institute of Cancer Research), Shivangi Wani, Milena Gongora(Queen Elizabeth University Hospital), Matthew J. Anderson, Oliver Holmes(University of Glasgow), Conrad Leonard, Darrin F. Taylor(The University of Melbourne), Scott Wood, Christina Xu, Kátia Nones(Glasgow Royal Infirmary), J. Lynn Fink(Heidelberg University), Angelika N. Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Michael C. Quinn, Shivashankar H. Nagaraj, Stephen H. Kazakoff, Nick M. Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher W. Toon(Universitätsklinikum Erlangen), Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor(Institute of Cancer Research), Vincent Lam, Duncan McLeod, Henry Pleass, A. J. Richardson(Glasgow Royal Infirmary), Virginia James, James G. Kench, Caroline Cooper, David Joseph, Charbel Sandroussi(Institute of Cancer Research), Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna Epari, Mo Ballal, David Fletcher(Cancer Research UK), Sanjay Mukhedkar, Nigel Spry, Bastiaan DeBoer, Ming G. Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney(Glasgow Royal Infirmary), Nan Q. Nguyen, Andrew Ruszkiewicz(University of Michigan), Chris Worthley, Chuan Tan, Tamara Debrencini, John Chen(Glasgow Royal Infirmary), Mark E. Brooke‐Smith, Virginia Papangelis(Cancer Research UK), Henry H. K. Tang, Andrew P. Barbour, Andrew D. Clouston(Glasgow Royal Infirmary), Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson(Universitätsklinikum Erlangen), Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio–Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni(Heidelberg University), Claudio Bassi(Institute of Cancer Research), Margaret A. Tempero, Craig Nourse(Cancer Research UK), Nigel B. Jamieson(Glasgow Royal Infirmary), Janet S. Graham, Marina Pajic(Garvan Institute of Medical Research), Elizabeth A. Musgrove(University of Glasgow), Gloria M. Petersen(Mayo Clinic in Arizona), Emma Shanks(Cancer Research UK), Alan Ashworth(Breast Cancer Now), Howard C. Crawford(University of Michigan), Diane M. Simeone(NYU Langone Health), Fieke E. M. Froeling(Cold Spring Harbor Laboratory), Christopher J. Lord(Institute of Cancer Research), Debabrata Mukhopadhyay(Jacksonville College), Christian Pilarsky(Universitätsklinikum Erlangen), Sean E. Grimmond(The University of Melbourne), Jennifer P. Morton(Cancer Research UK Scotland Institute), Owen J. Sansom(Cancer Research UK), David K. Chang(Glasgow Royal Infirmary), Peter J. Bailey(Heidelberg University), Andrew V. Biankin(University of Glasgow)
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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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