期刊
CELL REPORTS
卷 31, 期 6, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.107625
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资金
- National Health and Medical Research Council of Australia (NHMRC) [631701, 535903, 427601]
- American Association for Cancer Research (AACR) Landon Foundation-INNOVATOR Award
- NIH [5R01CA150190-07, P50 CA102701, U01 CA224145]
- NHMRC [1162860, 1162556]
- Cancer Australia [1143699]
- Cancer Research UK [C29717/A17263, C29717/A18484, C596/A18076, C596/A20921, A23526, A14276, A25233, A29996]
- Wellcome Trust [103721/Z/14/Z]
- Pancreatic Cancer UK Future Research Leaders Fund [FLF2015_04_Glasgow]
- Pancreatic Cancer Research Fund
- MRC/EPSRC Glasgow Molecular Pathology Node
- Italian Cancer Genome Project-Ministry of University (FIRB RBAP10AHJB)
- Associazione Italiana Ricerca Cancro [12182]
- FP7 European Community [602783]
- Italian Ministry of Health [FIMP-CUP_ J33G13000210001]
- ICGC Ontario Institute for Cancer Research
- CRUK Glasgow Centre [A25142]
- Core Services at the Cancer Research UK Beatson Institute [A17196]
- Susan Wojcicki and Dennis Tropper NIH grant [CA62924]
- Scottish Genome Partnership [SEHHD-CSO 1175759/2158447]
- Howat Foundation
- National Health and Medical Research Council of Australia [1162860, 1162556] Funding Source: NHMRC
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 (GSK3 beta) a key regulator of glycolysis. Pharmacological inhibition of GSK3 beta 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 GSK3 beta 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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