HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosanna Upstill‐Goddard, Ulla‐Maja Bailey, Ian Garner, Craig Nourse, Stephan B. Dreyer, Marc D. Jones, Kim Moran‐Jones, Derek Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephen J. Pettitt, Michele Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Sarah Allison, Andrew V. Biankin, David K. Chang, Susanna L. Cooke, Stephan B. Dreyer, Paul Grimwood, Shane Kelly, John L. Marshall, Brian McDade, Daniel L. McElroy, Donna Ramsay, Rosanna Upstill‐Goddard, Selma Rebus, Jane Hair, Nigel B. Jamieson, Colin J. McKay, Paul Westwood, Nicola Williams, Fraser R. Duthie, Andrew V. Biankin, Amber L. Johns, Amanda Mawson, David K. Chang, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, 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, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew J. Anderson, Oliver Holmes, Conrad Leonard, Darrin F. Taylor, Scott Wood, Christina Xu, Kátia Nones, J. Lynn Fink
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.