Journal article
HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
H Brunton, G Caligiuri, R Cunningham, R Upstill-Goddard, UM Bailey, IM Garner, C Nourse, S Dreyer, M Jones, K Moran-Jones, DW Wright, V Paulus-Hock, C Nixon, G Thomson, NB Jamieson, GA McGregor, L Evers, CJ McKay, A Gulati, R Brough Show all
Cell Reports | CELL PRESS | Published : 2020
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..
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Awarded by Merck KGaA
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (NHMRC; grants 631701, 535903, and 427601); American Association for Cancer Research (AACR) Landon Foundation-INNOVATOR Award; Susan Wojcicki and Dennis Tropper NIH grant CA62924; NIH (grants 5R01CA150190-07, P50 CA102701, and U01 CA224145); NHMRC (grants 1162860 and 1162556); Cancer Australia (grant 1143699); Cancer Research UK (grants C29717/A17263, C29717/A18484, C596/A18076, C596/A20921, A23526, A14276, A25233, and A29996); Wellcome Trust Senior Investigator Award (103721/Z/14/Z); Pancreatic Cancer UK Future Research Leaders Fund (FLF2015_04_Glasgow); Scottish Genome Partnership (SEHHD-CSO 1175759/2158447); Pancreatic Cancer Research Fund; MRC/EPSRC Glasgow Molecular Pathology Node; The Howat Foundation; Italian Cancer Genome Project-Ministry of University (FIRB RBAP10AHJB); Associazione Italiana Ricerca Cancro (grant 12182); FP7 European Community Grant Cam-Pac (grant 602783); Italian Ministry of Health (FIMP-CUP_ J33G13000210001); and ICGC Ontario Institute for Cancer Research. The mass spectrometry analysis was carried out at Glasgow Polyomics (University of Glasgow). The PDCLs were provided by the Australian Pancreatic Cancer Genome Initiative (APGI; https://www.pancreaticcancer.net.au/) and the Garvin Institute of Medical Research (Sydney, Australia). We would like to thank the CRUK Glasgow Centre (A25142) and Core Services at the Cancer Research UK Beatson Institute (A17196), with particular thanks to the Biological Services Unit and Histology. We are thankful to Catherine Winchester for editing the manuscript and to Kevin Ryan for insightful commentary.