Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer.
Epithelial transport of ions and water
Fibrosis
Homeostasis
Metabolism
Oncology
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
09 Oct 2023
09 Oct 2023
Historique:
received:
28
03
2023
accepted:
24
08
2023
medline:
3
11
2023
pubmed:
29
8
2023
entrez:
29
8
2023
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH was sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding, focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially altered the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreased when mice received the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifted from granulocyte rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.
Identifiants
pubmed: 37643024
pii: 170928
doi: 10.1172/jci.insight.170928
pmc: PMC10619433
doi:
pii:
Substances chimiques
cariporide
7E3392891K
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Références
Nucleic Acids Res. 2015 Sep 3;43(15):e97
pubmed: 25925576
Nat Metab. 2020 Jan;2(1):62-80
pubmed: 32694686
Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):487-505
pubmed: 32393771
Ann Thorac Surg. 2008 Apr;85(4):1261-70
pubmed: 18355507
Genes Dev. 2001 Dec 15;15(24):3243-8
pubmed: 11751630
Oncogene. 2014 Jun 5;33(23):2956-67
pubmed: 23851493
Cancers (Basel). 2021 Feb 03;13(4):
pubmed: 33546284
Theranostics. 2021 Jan 1;11(3):1295-1309
pubmed: 33391535
J Immunol. 2022 Jul 1;209(1):136-144
pubmed: 35715008
Front Physiol. 2020 Feb 14;11:89
pubmed: 32116794
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
pubmed: 12184808
Cancers (Basel). 2020 Sep 02;12(9):
pubmed: 32887220
Mol Biol Cell. 2011 Feb 1;22(3):421-36
pubmed: 21148289
Cancers (Basel). 2023 May 26;15(11):
pubmed: 37296886
Cancer Cell. 2014 Jun 16;25(6):735-47
pubmed: 24856585
Front Pharmacol. 2021 Jan 19;11:586599
pubmed: 33841132
Genesis. 2000 Feb;26(2):143-4
pubmed: 10686611
Int J Cancer. 2023 Mar 15;152(6):1210-1225
pubmed: 36408933
Physiology (Bethesda). 2013 Nov;28(6):380-90
pubmed: 24186933
Nucleic Acids Res. 2018 Jul 2;46(W1):W537-W544
pubmed: 29790989
J Exp Med. 2017 Mar 6;214(3):579-596
pubmed: 28232471
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
PLoS One. 2017 Nov 9;12(11):e0187552
pubmed: 29121082
Nature. 2001 Apr 26;410(6832):1111-6
pubmed: 11323676
J Cell Sci. 2017 Feb 15;130(4):663-669
pubmed: 28202602
Nature. 2022 Nov;611(7935):365-373
pubmed: 36323783
Oncotarget. 2017 Nov 28;8(68):112268-112282
pubmed: 29348824
World J Gastroenterol. 2015 Mar 7;21(9):2807-15
pubmed: 25759553
Neoplasia. 2015 Feb;17(2):155-66
pubmed: 25748234
Adv Physiol Educ. 2004 Dec;28(1-4):160-79
pubmed: 15545345
Surgery. 1994 Apr;115(4):503-9
pubmed: 8165542
Gastroenterology. 1998 Aug;115(2):421-32
pubmed: 9679048
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Bioessays. 2017 Jun;39(6):
pubmed: 28440551
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):459-63
pubmed: 18182493
Biochem Cell Biol. 2014 Dec;92(6):530-40
pubmed: 25275700
Cancers (Basel). 2023 Apr 30;15(9):
pubmed: 37174038
Cancer Discov. 2022 Feb;12(2):484-501
pubmed: 34548310
J Transl Med. 2013 Nov 06;11:282
pubmed: 24195657
Cell. 2004 Dec 17;119(6):847-60
pubmed: 15607980
Cancers (Basel). 2021 Feb 09;13(4):
pubmed: 33572223
Bioinformatics. 2017 Feb 1;33(3):414-424
pubmed: 27694195
Sci Rep. 2014 Mar 19;4:4410
pubmed: 24642931
Cell. 2014 Sep 25;159(1):80-93
pubmed: 25259922
Nat Mater. 2020 Sep;19(9):1019-1025
pubmed: 32451510
J Physiol. 2005 Aug 15;567(Pt 1):225-38
pubmed: 15946960
J Physiol. 2005 Oct 15;568(Pt 2):445-58
pubmed: 16037087
Curr Med Chem. 2012;19(5):647-60
pubmed: 22204338
J Pathol. 2021 Jan;253(1):80-93
pubmed: 32985688
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19609-19618
pubmed: 31484774
Semin Cancer Biol. 2017 Apr;43:5-16
pubmed: 28007556
Eur Biophys J. 2016 Oct;45(7):657-670
pubmed: 27670661
Biophys J. 2020 Dec 1;119(11):2141-2152
pubmed: 33264597
Front Physiol. 2013 Dec 20;4:380
pubmed: 24391597
Nat Commun. 2020 Jul 8;11(1):3409
pubmed: 32641778
Cancers (Basel). 2020 Dec 15;12(12):
pubmed: 33333727
Cancer Cell. 2003 Dec;4(6):437-50
pubmed: 14706336
FASEB J. 2018 Feb;32(2):1099-1107
pubmed: 29070586
Nat Cancer. 2022 Dec;3(12):1464-1483
pubmed: 36522548
J Card Surg. 2003 Jan-Feb;18 Suppl 1:13-20
pubmed: 12691375
Front Physiol. 2019 Mar 12;10:218
pubmed: 30930789
Gut. 1998 Jul;43(1):128-33
pubmed: 9771417
J Biol Chem. 2015 Feb 20;290(8):5167-5173
pubmed: 25561736
Cell Rep. 2014 Sep 25;8(6):1793-1807
pubmed: 25220458