Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
06 Nov 2023
06 Nov 2023
Historique:
received:
28
03
2023
accepted:
26
10
2023
revised:
23
10
2023
medline:
7
11
2023
pubmed:
7
11
2023
entrez:
6
11
2023
Statut:
epublish
Résumé
Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.
Identifiants
pubmed: 37932309
doi: 10.1038/s41389-023-00497-9
pii: 10.1038/s41389-023-00497-9
pmc: PMC10628277
doi:
Types de publication
Journal Article
Langues
eng
Pagination
51Informations de copyright
© 2023. The Author(s).
Références
Cancer Lett. 2013 Nov 28;341(1):56-62
pubmed: 23830804
Cell. 2018 May 3;173(4):879-893.e13
pubmed: 29681456
Cell Death Dis. 2017 Aug 10;8(8):e2980
pubmed: 28796259
Cell Rep. 2017 May 23;19(8):1669-1684
pubmed: 28538184
J Clin Oncol. 2010 Sep 1;28(25):4006-12
pubmed: 20498387
Cancer Res. 2005 Jul 1;65(13):5506-11
pubmed: 15994920
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5429-38
pubmed: 25453096
Breast Dis. 2010;32(1-2):35-48
pubmed: 21778573
Oncogene. 2016 Sep 8;35(36):4787-97
pubmed: 26876203
FEBS Lett. 1999 Sep 10;458(1):77-80
pubmed: 10518938
Cell Death Dis. 2021 Feb 24;12(2):207
pubmed: 33627632
Biomaterials. 2012 Jan;33(2):679-91
pubmed: 22019123
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Br J Cancer. 2016 Aug 9;115(4):431-41
pubmed: 27415012
Nature. 2005 Jul 28;436(7050):518-24
pubmed: 16049480
Nat Rev Clin Oncol. 2011 Jan;8(1):12-23
pubmed: 20859283
Mol Biol Cell. 2014 Sep 15;25(18):2677-81
pubmed: 25213191
Nat Biotechnol. 2016 Apr;34(4):419-23
pubmed: 26928769
Nat Rev Cancer. 2005 Apr;5(4):275-84
pubmed: 15803154
Nature. 2015 May 28;521(7553):489-94
pubmed: 26017449
Oncogene. 2022 Apr;41(14):2069-2078
pubmed: 35177812
Cancer Lett. 2016 Mar 28;372(2):147-56
pubmed: 26797015
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
pubmed: 12629218
Mol Cancer Res. 2020 Sep;18(9):1257-1270
pubmed: 32503922
PLoS One. 2013 Apr 09;8(4):e61071
pubmed: 23593394
J Med Genet. 2004 Nov;41(11):826-36
pubmed: 15520407
Clin Cancer Res. 2013 May 15;19(10):2723-33
pubmed: 23549873
Nat Commun. 2021 May 24;12(1):3055
pubmed: 34031411
J Biol Chem. 1994 Oct 21;269(42):26486-91
pubmed: 7929370
Blood. 2014 Sep 4;124(10):1553-62
pubmed: 25049281
Oncotarget. 2017 Jul 6;8(35):59950-59964
pubmed: 28938696
Nature. 2015 Jan 1;517(7532):81-4
pubmed: 25327250
Cancer Cell. 2007 Mar;11(3):259-73
pubmed: 17349583
Nat Cancer. 2020 Apr;1(4):410-422
pubmed: 34109316
Cancer Biol Med. 2015 Jun;12(2):106-16
pubmed: 26175926
Genome Biol. 2014;15(12):554
pubmed: 25476604
Cell Rep. 2014 Feb 13;6(3):417-9
pubmed: 24529750
Cancer Cell. 2007 Jun;11(6):498-512
pubmed: 17560332
Oncogene. 2015 Feb 5;34(6):681-90
pubmed: 24531710
Trends Pharmacol Sci. 2016 Jun;37(6):451-462
pubmed: 27068431
Expert Opin Ther Targets. 2016 Jun;20(6):705-20
pubmed: 26607563
Nat Med. 2017 Jan;23(1):60-68
pubmed: 27869803
Nat Protoc. 2017 Apr;12(4):828-863
pubmed: 28333914
J Invest Dermatol. 2008 Apr;128(4):957-71
pubmed: 17943188
N Engl J Med. 2010 Nov 11;363(20):1938-48
pubmed: 21067385
Clin Cancer Res. 2009 Jun 15;15(12):4234-41
pubmed: 19509181
Nat Rev Cancer. 2013 Oct;13(10):727-38
pubmed: 24060864
Breast Cancer Res. 2014 Aug 08;16(4):406
pubmed: 25103565
Skelet Muscle. 2014 Oct 24;4:19
pubmed: 25789155
Nature. 2015 Nov 26;527(7579):472-6
pubmed: 26560033
JAMA Oncol. 2021 Jan 01;7(1):61-69
pubmed: 33151286
Br J Cancer. 2018 Dec;119(12):1495-1507
pubmed: 30482914
Nature. 2012 Apr 04;486(7403):395-9
pubmed: 22495314
Cell Death Dis. 2019 Mar 20;10(4):270
pubmed: 30894512
Cell. 2012 Jul 6;150(1):165-78
pubmed: 22770218
Nature. 2015 Jan 8;517(7533):209-13
pubmed: 25470039
Cancer Res. 2009 Oct 1;69(19):7507-11
pubmed: 19752085
Breast Cancer Res Treat. 2017 Jun;163(3):461-474
pubmed: 28341962
N Engl J Med. 2017 Dec 7;377(23):2287-2289
pubmed: 29211674
Nat Biotechnol. 2016 Jun;34(6):634-6
pubmed: 27159373
Cell Res. 2019 Nov;29(11):875-876
pubmed: 31619763
Science. 2013 Feb 15;339(6121):819-23
pubmed: 23287718
Curr Treat Options Oncol. 2012 Jun;13(2):263-75
pubmed: 22528367
Cancer Res. 2021 Mar 1;81(5):1332-1346
pubmed: 33372040
Nature. 2012 Jan 11;481(7382):506-10
pubmed: 22237025