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ABSTRACT: 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
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
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
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.
SUBMITTER: Betzler AM
PROVIDER: S-EPMC7919037 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Betzler Alexander M AM Nanduri Lahiri K LK Hissa Barbara B Blickensdörfer Linda L Muders Michael H MH Roy Janine J Jesinghaus Moritz M Steiger Katja K Weichert Wilko W Kloor Matthias M Klink Barbara B Schroeder Michael M Mazzone Massimiliano M Weitz Jürgen J Reissfelder Christoph C Rahbari Nuh N NN Schölch Sebastian S
Cancers 20210215 4
<h4>Background</h4>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.<h4>Methods</h4>Tumors were induced in mice with conditional mutations or knockouts i ...[more]