HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.
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ICR Authors
Authors
Brunton, H
Caligiuri, G
Cunningham, R
Upstill-Goddard, R
Bailey, U-M
Garner, IM
Nourse, C
Dreyer, S
Jones, M
Moran-Jones, K
Wright, DW
Paulus-Hock, V
Nixon, C
Thomson, G
Jamieson, NB
McGregor, GA
Evers, L
McKay, CJ
Gulati, A
Brough, R
Bajrami, I
Pettitt, SJ
Dziubinski, ML
Barry, ST
Grützmann, R
Brown, R
Curry, E
Glasgow Precision Oncology Laboratory,
Australian Pancreatic Cancer Genome Initiative,
Pajic, M
Musgrove, EA
Petersen, GM
Shanks, E
Ashworth, A
Crawford, HC
Simeone, DM
Froeling, FEM
Lord, CJ
Mukhopadhyay, D
Pilarsky, C
Grimmond, SE
Morton, JP
Sansom, OJ
Chang, DK
Bailey, PJ
Biankin, AV
Caligiuri, G
Cunningham, R
Upstill-Goddard, R
Bailey, U-M
Garner, IM
Nourse, C
Dreyer, S
Jones, M
Moran-Jones, K
Wright, DW
Paulus-Hock, V
Nixon, C
Thomson, G
Jamieson, NB
McGregor, GA
Evers, L
McKay, CJ
Gulati, A
Brough, R
Bajrami, I
Pettitt, SJ
Dziubinski, ML
Barry, ST
Grützmann, R
Brown, R
Curry, E
Glasgow Precision Oncology Laboratory,
Australian Pancreatic Cancer Genome Initiative,
Pajic, M
Musgrove, EA
Petersen, GM
Shanks, E
Ashworth, A
Crawford, HC
Simeone, DM
Froeling, FEM
Lord, CJ
Mukhopadhyay, D
Pilarsky, C
Grimmond, SE
Morton, JP
Sansom, OJ
Chang, DK
Bailey, PJ
Biankin, AV
Document Type
Journal Article
Date
2020-05-12
Date Accepted
2020-04-17
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.
Citation
Cell reports, 2020, 31 (6), pp. 107625 - ?
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Research Team
Medicine (Brown Epigenetic Therapy)
Gene Function
Gene Function