NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy.
NOTCH
STAT3
chemoradiotherapy
gastrointestinal cancer
treatment resistance
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
26 Jan 2021
26 Jan 2021
Historique:
received:
18
12
2020
revised:
21
01
2021
accepted:
22
01
2021
entrez:
3
2
2021
pubmed:
4
2
2021
medline:
4
2
2021
Statut:
epublish
Résumé
Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.
Identifiants
pubmed: 33530306
pii: cancers13030455
doi: 10.3390/cancers13030455
pmc: PMC7865718
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : GR 3376/4-1, WI 1704/5-1, TRR130, CRC877, CRC841
Références
Clin Cancer Res. 2011 Mar 15;17(6):1452-62
pubmed: 21310826
Nat Cell Biol. 2004 Jun;6(6):547-54
pubmed: 15156153
Int J Surg Pathol. 2012 Apr;20(2):139-45
pubmed: 22084425
Lancet Oncol. 2012 Sep;13(9):e403-8
pubmed: 22935240
Nat Rev Urol. 2011 Jan;8(1):51-7
pubmed: 21135876
Cancer Res. 2017 Feb 15;77(4):960-970
pubmed: 27923831
Cancer Cell. 2004 May;5(5):429-41
pubmed: 15144951
Lancet Oncol. 2015 Jan;16(1):e13-22
pubmed: 25638548
Mol Immunol. 2019 Oct;114:30-40
pubmed: 31336247
Cancer Cell. 2014 Mar 17;25(3):318-34
pubmed: 24651013
Carcinogenesis. 2011 Dec;32(12):1824-31
pubmed: 21983179
Nat Rev Cancer. 2014 Nov;14(11):736-46
pubmed: 25342631
N Engl J Med. 2004 Oct 21;351(17):1731-40
pubmed: 15496622
J Natl Cancer Inst. 2017 Dec 1;109(12):
pubmed: 29206996
Nat Rev Cancer. 2019 Feb;19(2):82-96
pubmed: 30578415
Oncol Lett. 2015 Nov;10(5):3252-3260
pubmed: 26722321
Oncotarget. 2016 Feb 16;7(7):7610-28
pubmed: 26713603
Semin Radiat Oncol. 2015 Oct;25(4):227-36
pubmed: 26384271
Nat Rev Immunol. 2018 Dec;18(12):773-789
pubmed: 30254251
Cancer Res. 2006 Mar 15;66(6):2913-7
pubmed: 16540637
Mol Cell Biol. 1997 Aug;17(8):4677-86
pubmed: 9234724
J Clin Oncol. 2014 May 20;32(15):1554-62
pubmed: 24752056
Cancer. 2012 Aug 15;118(16):4074-89
pubmed: 22213175
J Exp Med. 2020 May 4;217(5):
pubmed: 32267936
J Clin Oncol. 2015 Jun 1;33(16):1797-808
pubmed: 25918296
Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270
pubmed: 29397354
Sci Rep. 2019 Jul 25;9(1):10811
pubmed: 31346210
Int J Cancer. 2014 Feb 15;134(4):997-1007
pubmed: 23934972
Lancet. 2010 Mar 20;375(9719):1030-47
pubmed: 20304247
J Cell Mol Med. 2019 Jun;23(6):4005-4018
pubmed: 30993885
Cell. 2009 Apr 17;137(2):216-33
pubmed: 19379690
J Cancer. 2020 Jan 20;11(7):1859-1868
pubmed: 32194797
Curr Opin Immunol. 2015 Jun;34:75-82
pubmed: 25749511
Lancet Oncol. 2012 Jul;13(7):679-87
pubmed: 22627104
Nat Rev Clin Oncol. 2018 Apr;15(4):234-248
pubmed: 29405201
Nat Protoc. 2006;1(5):2315-9
pubmed: 17406473
Mol Cancer Res. 2017 Nov;15(11):1481-1490
pubmed: 28811361
Lancet. 2018 Jun 23;391(10139):2537-2545
pubmed: 29976470
Cancer. 2020 Jul 15;126(14):3360-3371
pubmed: 32383803
Lancet. 2013 Feb 2;381(9864):400-12
pubmed: 23374478
Cancer Lett. 2017 Apr 1;390:115-125
pubmed: 28108315
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44
pubmed: 25605917
Langenbecks Arch Surg. 2012 Apr;397(4):543-55
pubmed: 22382702
PLoS One. 2015 Dec 09;10(12):e0144322
pubmed: 26650241
JAMA Oncol. 2019 Apr 1;5(4):e185896
pubmed: 30629084
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Immunity. 2019 Jul 16;51(1):27-41
pubmed: 31315034
Cancer Res. 2016 Mar 1;76(5):994-8
pubmed: 26880806
Aging (Albany NY). 2020 Feb 6;12(3):2595-2609
pubmed: 32028262
Nat Rev Cancer. 2015 Jul;15(7):409-25
pubmed: 26105538
Lancet Oncol. 2018 Nov;19(11):1459-1467
pubmed: 30348537
Nat Biotechnol. 1997 Feb;15(2):142-5
pubmed: 9035138
Nat Med. 2019 Oct;25(10):1607-1614
pubmed: 31591597
Cancer. 1992 Jan 15;69(2):277-84
pubmed: 1728357
JAMA Surg. 2020 Jul 1;155(7):657-658
pubmed: 32347912
Nat Rev Gastroenterol Hepatol. 2020 May;17(5):298-313
pubmed: 32005946
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2237-2242
pubmed: 30670657
EMBO Mol Med. 2017 Feb;9(2):137-153
pubmed: 28028012
J Interferon Cytokine Res. 1997 Mar;17(3):121-34
pubmed: 9085936
Nat Rev Cancer. 2011 Apr;11(4):239-53
pubmed: 21430696
Clin Cancer Res. 2017 Oct 1;23(19):5881-5891
pubmed: 28720669
Nat Rev Immunol. 2007 Jun;7(6):454-65
pubmed: 17525754