Differential Effects of Trp53 Alterations in Murine Colorectal Cancer.
Apc
GEMM
Kras
TP53
Trp53
adenovirus
colorectal cancer
genetically engineered mouse model
metastasis
preclinical studies
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
15 Feb 2021
15 Feb 2021
Historique:
received:
18
01
2021
revised:
05
02
2021
accepted:
08
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
7
3
2021
Statut:
epublish
Résumé
Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.
Sections du résumé
BACKGROUND
BACKGROUND
Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.
METHODS
METHODS
Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.
RESULTS
RESULTS
The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.
CONCLUSIONS
CONCLUSIONS
This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.
Identifiants
pubmed: 33671932
pii: cancers13040808
doi: 10.3390/cancers13040808
pmc: PMC7919037
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : WE 3548/4-1
Organisme : Roland Ernst Stiftung
ID : RES 1/14
Références
Science. 1992 May 1;256(5057):668-70
pubmed: 1350108
J Vis Exp. 2017 Jul 18;(125):
pubmed: 28745637
Nat Rev Drug Discov. 2006 Sep;5(9):741-54
pubmed: 16915232
Neoplasia. 2008 Jul;10(7):680-6, 2 p following 686
pubmed: 18592002
Crit Rev Oncol Hematol. 2017 Jan;109:9-19
pubmed: 28010901
Cancer. 1992 Sep 15;70(6 Suppl):1727-31
pubmed: 1516027
Cancer Res. 2005 Nov 15;65(22):10280-8
pubmed: 16288016
Trends Pharmacol Sci. 2012 Aug;33(8):449-55
pubmed: 22739258
Cancers (Basel). 2012 Nov 08;4(4):1180-211
pubmed: 24213504
Oncoimmunology. 2015 May 7;4(11):e1042201
pubmed: 26451314
J Clin Oncol. 2000 Aug;18(16):2938-47
pubmed: 10944126
Cancer Res. 2012 Jun 1;72(11):2695-700
pubmed: 22593194
Nat Biotechnol. 2010 Jun;28(6):585-93
pubmed: 20495549
Oncotarget. 2015 Mar 10;6(7):4663-76
pubmed: 25609199
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11859-11864
pubmed: 27708166
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Cancer Res. 2014 Jul 15;74(14):3857-69
pubmed: 24860162
Clin Cancer Res. 2013 May 15;19(10):2688-98
pubmed: 23549875
Nature. 2001 Apr 26;410(6832):1111-6
pubmed: 11323676
EMBO Mol Med. 2015 Aug 19;7(10):1350-65
pubmed: 26290450
Cancer Res. 2014 Oct 15;74(20):5690-9
pubmed: 25038229
Gastroenterology. 2019 Dec;157(6):1599-1614.e2
pubmed: 31585123
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1565-70
pubmed: 20080688
PLoS Genet. 2006 Sep 15;2(9):e146
pubmed: 17002498
Nucleic Acids Res. 2016 Jan 4;44(D1):D481-7
pubmed: 26656494
Nat Med. 2013 May;19(5):614-8
pubmed: 23584090
Gastroenterology. 2012 Feb;142(2):219-32
pubmed: 22155636
Genes Dev. 2000 Apr 15;14(8):994-1004
pubmed: 10783170
Science. 1997 Oct 3;278(5335):120-3
pubmed: 9311916
Cell. 2004 Dec 17;119(6):847-60
pubmed: 15607980
Mol Carcinog. 2015 Nov;54(11):1376-86
pubmed: 25213383
Cancers (Basel). 2020 Dec 15;12(12):
pubmed: 33333841
Nature. 1992 Sep 17;359(6392):235-7
pubmed: 1528264
J Pathol. 2011 Jan;223(2):116-26
pubmed: 21125670
Br J Cancer. 1978 May;37(5):833-40
pubmed: 656310
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
J Vis Exp. 2017 Jul 6;(125):
pubmed: 28715385
Nat Genet. 2006 Aug;38(8):888-95
pubmed: 16862160
Cancer Res. 2014 Mar 15;74(6):1694-704
pubmed: 24599131
Diagnostics (Basel). 2020 May 15;10(5):
pubmed: 32429174
J Cancer. 2017 Apr 9;8(7):1187-1196
pubmed: 28607593
Oncotarget. 2016 May 10;7(19):27232-42
pubmed: 27029058
Gastroenterology. 2013 Apr;144(4):705-17
pubmed: 23415801
Gastroenterology. 2003 Mar;124(3):762-77
pubmed: 12612914
Mod Pathol. 2007 Dec;20(12):1286-97
pubmed: 17906616