High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1.
CSF-1
Pancreatic ductal adenocarcinoma
collagen
deactivation
pancreatic stellate cells
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 05 2020
06 05 2020
Historique:
received:
02
07
2019
revised:
11
02
2020
accepted:
18
02
2020
pubmed:
17
3
2020
medline:
28
4
2021
entrez:
17
3
2020
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.
Identifiants
pubmed: 32173982
doi: 10.15252/embr.201948780
pmc: PMC7202203
doi:
Substances chimiques
Macrophage Colony-Stimulating Factor
81627-83-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e48780Subventions
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : UVA 2013-5932
Pays : International
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : UVA 2012-5607
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
Références
J Cell Biol. 2004 Apr 26;165(2):263-73
pubmed: 15117969
Cancer Cell. 2014 Jun 16;25(6):735-47
pubmed: 24856585
Am J Pathol. 2009 Aug;175(2):636-48
pubmed: 19608876
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Mol Cancer. 2018 Jul 30;17(1):108
pubmed: 30060755
J Clin Oncol. 2018 Feb 1;36(4):359-366
pubmed: 29232172
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
Mol Cell Biol. 1987 Jul;7(7):2378-87
pubmed: 3039346
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2237-2242
pubmed: 30670657
Int J Cancer. 2019 Nov 15;145(10):2792-2803
pubmed: 31018252
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
J Pathol. 2013 May;230(1):107-17
pubmed: 23359139
Nat Commun. 2017 Jul 07;8:16031
pubmed: 28685754
Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L924-31
pubmed: 15821021
Clin Chem Lab Med. 2004 Mar;42(3):256-60
pubmed: 15080556
Curr Opin Cell Biol. 2013 Feb;25(1):30-8
pubmed: 23195437
J Pathol. 2019 May;248(1):51-65
pubmed: 30575030
Cancer Cell. 2014 Jun 16;25(6):719-34
pubmed: 24856586
PLoS One. 2011;6(11):e27450
pubmed: 22096574
Sci Rep. 2020 Jan 15;10(1):337
pubmed: 31941932
Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6140-6145
pubmed: 30850544
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Cancer Discov. 2019 Feb;9(2):282-301
pubmed: 30366930
Science. 2009 Jun 12;324(5933):1457-61
pubmed: 19460966
J Exp Med. 2014 Jul 28;211(8):1503-23
pubmed: 25071162
Cancers (Basel). 2019 Apr 26;11(5):
pubmed: 31035512
Nat Cell Biol. 2007 Dec;9(12):1392-400
pubmed: 18037882
Int J Biol Markers. 2012 Oct 08;27(3):e186-94
pubmed: 22865301
J Exp Med. 2017 Mar 6;214(3):579-596
pubmed: 28232471
Expert Rev Gastroenterol Hepatol. 2018 Apr;12(4):315-317
pubmed: 29495889
Gastroenterology. 2018 Dec;155(6):1999-2013.e3
pubmed: 30165049
EMBO Rep. 2020 May 6;21(5):e48780
pubmed: 32173982
Nat Med. 2007 Sep;13(9):1070-7
pubmed: 17767167
Mol Cell Biol Res Commun. 1999 May;1(2):144-52
pubmed: 10356364
Mol Cell Biol. 1988 Nov;8(11):5035-9
pubmed: 3264878
Gastroenterology. 2011 Oct;141(4):1486-97, 1497.e1-14
pubmed: 21704588
BMC Cancer. 2016 Aug 12;16:632
pubmed: 27520560
Cold Spring Harb Perspect Biol. 2014 Jun 02;6(6):
pubmed: 24890514
Front Physiol. 2014 Apr 09;5:141
pubmed: 24782785
PLoS One. 2013 Aug 05;8(8):e71189
pubmed: 23940715
Nat Commun. 2013;4:2516
pubmed: 24084631
Mol Cancer. 2019 Mar 30;18(1):48
pubmed: 30925924
Neoplasia. 2009 May;11(5):497-508
pubmed: 19412434
Cancer Metastasis Rev. 2015 Mar;34(1):97-114
pubmed: 25566685
Immunity. 2012 Apr 20;36(4):503-14
pubmed: 22520844
J Clin Oncol. 2019 May 1;37(13):1062-1069
pubmed: 30817250
Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):380-4
pubmed: 21081113
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Cell Rep. 2018 May 1;23(5):1448-1460
pubmed: 29719257
Am J Pathol. 2019 Jan;189(1):44-57
pubmed: 30558722
Exp Dermatol. 2006 Apr;15(4):291-9
pubmed: 16512876
J Transl Med. 2015 Apr 11;13:115
pubmed: 25884700
Mol Biol Cell. 2000 Nov;11(11):3835-48
pubmed: 11071910
Cell. 2014 Sep 25;159(1):80-93
pubmed: 25259922
Cancer Cell. 2017 Aug 14;32(2):185-203.e13
pubmed: 28810144
Trends Cell Biol. 2004 Nov;14(11):628-38
pubmed: 15519852
Oncogene. 2009 Feb 5;28(5):773-80
pubmed: 18997822
Curr Top Microbiol Immunol. 2021;430:183-198
pubmed: 30790075
Gene Ther. 2010 Apr;17(4):511-20
pubmed: 20016542
N Engl J Med. 2014 Nov 27;371(22):2140-1
pubmed: 25427123
PLoS One. 2010 Sep 27;5(9):e13002
pubmed: 20885998
Gut. 2015 Sep;64(9):1476-84
pubmed: 25994217
Mol Cancer. 2019 Jan 21;18(1):14
pubmed: 30665410
Gastroenterology. 2015 Apr;148(4):849-50
pubmed: 25724458