TY - JOUR
T1 - Differential effects of trp53 alterations in murine colorectal cancer
AU - Betzler, Alexander M.
AU - Nanduri, Lahiri K.
AU - Hissa, Barbara
AU - Blickensdörfer, Linda
AU - Muders, Michael H.
AU - Roy, Janine
AU - Jesinghaus, Moritz
AU - Steiger, Katja
AU - Weichert, Wilko
AU - Kloor, Matthias
AU - Klink, Barbara
AU - Schroeder, Michael
AU - Mazzone, Massimiliano
AU - Weitz, Jürgen
AU - Reissfelder, Christoph
AU - Rahbari, Nuh N.
AU - Schölch, Sebastian
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - 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.
AB - 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.
KW - Adenovirus
KW - Apc
KW - Colorectal cancer
KW - GEMM
KW - Genetically engineered mouse model
KW - Kras
KW - Metastasis
KW - Preclinical studies
KW - TP53
KW - Trp53
UR - http://www.scopus.com/inward/record.url?scp=85100717961&partnerID=8YFLogxK
U2 - 10.3390/cancers13040808
DO - 10.3390/cancers13040808
M3 - Article
AN - SCOPUS:85100717961
SN - 2072-6694
VL - 13
SP - 1
EP - 15
JO - Cancers
JF - Cancers
IS - 4
M1 - 808
ER -