Inhibiting stromal Class I HDACs curbs pancreatic cancer progression.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Dec 2023
06 Dec 2023
Historique:
received:
13
04
2023
accepted:
27
09
2023
medline:
11
12
2023
pubmed:
7
12
2023
entrez:
6
12
2023
Statut:
epublish
Résumé
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
Identifiants
pubmed: 38057326
doi: 10.1038/s41467-023-42178-6
pii: 10.1038/s41467-023-42178-6
pmc: PMC10700526
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7791Subventions
Organisme : NCI NIH HHS
ID : R01 CA220468
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA265762
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA082683
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009370
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA217033
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Cold Spring Harb Perspect Med. 2016 Oct 3;6(10):
pubmed: 27599530
Cancer Cell. 2014 Jun 16;25(6):719-34
pubmed: 24856586
J Clin Invest. 2018 Jun 1;128(6):2389-2405
pubmed: 29733296
Cancer Res. 2016 May 1;76(9):2525-39
pubmed: 26980767
Cancer Discov. 2020 Feb;10(2):232-253
pubmed: 31699795
Cancer Cell. 2012 Mar 20;21(3):418-29
pubmed: 22439937
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Commun. 2021 Aug 26;12(1):5151
pubmed: 34446712
Nature. 2019 May;569(7754):131-135
pubmed: 30996350
Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3091-100
pubmed: 25024225
BMC Genomics. 2018 Jun 19;19(1):477
pubmed: 29914354
Genes Dev. 2016 Feb 15;30(4):355-85
pubmed: 26883357
Nat Rev Drug Discov. 2014 Sep;13(9):673-91
pubmed: 25131830
BMC Cancer. 2009 Nov 13;9:395
pubmed: 19912635
Clin Cancer Res. 2017 Sep 1;23(17):5187-5201
pubmed: 28698201
Nat Commun. 2019 Jul 11;10(1):3055
pubmed: 31296870
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1129-1134
pubmed: 28096419
Cancer Discov. 2019 Feb;9(2):282-301
pubmed: 30366930
Nat Biotechnol. 2013 Jan;31(1):46-53
pubmed: 23222703
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7
pubmed: 24277834
Science. 2009 Jun 12;324(5933):1457-61
pubmed: 19460966
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Cancer Cell. 2014 Jun 16;25(6):735-47
pubmed: 24856585
Oncol Rep. 2009 Jun;21(6):1439-47
pubmed: 19424621
Gut. 2019 Jan;68(1):159-171
pubmed: 30177543
Cancer Res. 2008 Feb 1;68(3):918-26
pubmed: 18245495
J Exp Med. 2017 Mar 6;214(3):579-596
pubmed: 28232471
Biochim Biophys Acta. 2012 Jan;1819(1):28-37
pubmed: 21978825
Nucleic Acids Res. 2017 Jun 20;45(11):6334-6349
pubmed: 28369619
Cancer Discov. 2019 Aug;9(8):1102-1123
pubmed: 31197017
Nature. 2022 Nov;611(7934):148-154
pubmed: 36171287
Nat Commun. 2021 Aug 27;12(1):5155
pubmed: 34453044
Cancer Immunol Res. 2018 Dec;6(12):1561-1577
pubmed: 30341213
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Cancer Res. 2014 Jun 1;74(11):2913-21
pubmed: 24840647
J Mol Cell Cardiol. 2016 Feb;91:52-60
pubmed: 26721596
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
CA Cancer J Clin. 2021 Jan;71(1):7-33
pubmed: 33433946
Curr Protoc Mol Biol. 2015 Jan 05;109:21.29.1-21.29.9
pubmed: 25559105
Nat Rev Cancer. 2020 Mar;20(3):174-186
pubmed: 31980749
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Cancer Discov. 2018 Sep;8(9):1112-1129
pubmed: 29853643
PLoS One. 2013 Sep 16;8(9):e74250
pubmed: 24066126
Cell. 2018 Apr 5;173(2):400-416.e11
pubmed: 29625055
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Bioinformatics. 2010 Apr 1;26(7):966-8
pubmed: 20147306
Cell. 2014 Sep 25;159(1):80-93
pubmed: 25259922
Nature. 2021 May;593(7860):575-579
pubmed: 33981032
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Nat Chem Biol. 2010 Mar;6(3):238-243
pubmed: 20139990
J Mol Cell Cardiol. 2016 Aug;97:153-61
pubmed: 27167848
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Gut. 2009 Oct;58(10):1399-409
pubmed: 19528037
J Gastrointest Cancer. 2011 Jun;42(2):85-92
pubmed: 21271301
J Clin Invest. 2011 Oct;121(10):4106-17
pubmed: 21926469
J Pharm Biomed Anal. 2007 Jan 17;43(2):784-7
pubmed: 16971082
Clin Cancer Res. 2017 Apr 1;23(7):1647-1655
pubmed: 28373363
J Cell Mol Med. 2010 Jun;14(6A):1255-63
pubmed: 19929947
Oncotarget. 2017 Mar 21;8(12):19074-19088
pubmed: 27894105
Front Physiol. 2012 Aug 28;3:344
pubmed: 22973234
Int J Cancer. 2007 Sep 1;121(5):1138-48
pubmed: 17455259
J Biol Chem. 2013 Nov 8;288(45):32517-32527
pubmed: 24089530
Gut. 1998 Jul;43(1):128-33
pubmed: 9771417
J Control Release. 2022 Dec;352:1134-1143
pubmed: 36372388
Nat Med. 2015 Oct;21(10):1163-71
pubmed: 26390243
Pancreas. 2008 Apr;36(3):e1-9
pubmed: 18362831