The inducible KPC:APC mouse model for studying colon carcinogenesis in vivo and ex vivo

authors

• Gomot Mélissandre
• Essakhi Nora
• Codan Clément
• Pascal Quentin
• Klokov Dmitry
• Vares Guillaume

keywords

• KPCAPC
• Colon organoid
• Carcinogenesis

abstract

Introduction The B6.Cg-Krastm4Tyj Apctm1Tno Tg(CDX2-cre/ERT2)752Erf/MaraJ mouse model (referred to as KPC:APC) recapitulates colon carcinogenesis through the chromosomal instability pathway via inducible Apc and Kras mutations in Cdx2-expressing intestinal cells (Maitra et al., 2019). Following induction with tamoxifen, KPC:APC mice develop tumors resembling human colon cancer. However, further investigations are needed to better characterize the time course and characteristics of tumor development. Furthermore, we developed an ex vivo inducible colorectal cancer model derived from the KPC:APC mouse to study cellular and molecular pathways involved in Apc-Kras-driven colon carcinogenesis. Material and Methods Apc and/or Kras mutations were induced in adult KPC:APC mice via single or repeated 10 to 20 mg/kg intraperitoneal tamoxifen administration. Tumor development was histologically assessed between 4 and 12 weeks post induction. Using intestinal crypts extracted from KPC:APC mice, we developed 3D organoids to perform cellular and molecular characterizations. Results and Discussions Tumor development was highly dependent on tamoxifen administration regimen and mouse genotype (mutations in Kras and/or Apc genes). Apc mutation induction alone resulted in hyperplasia and dysplastic lesions, while the co-induction of Apc and Kras mutations accelerated adenoma development. Regardless of the genotype, lesions remained primarily restricted to the colon. KPC:APC mouse organoids were treated with tamoxifen to induce tumorigenesis. Conclusion Here we show that the KPC:APC mouse model is a relevant model for colon cancer research with its inducibility allowing for the coexistence of Apc and Kras mutation and its lesions mainly contained to the colon. Enhanced knowledge on tumor development will allow investigations on the effects of stressors (such as medical diagnostic exposures to low dose radiation) on colon carcinogenesis. The establishment of an ex vivo model combined with the fully characterized in vivo model provides the opportunity to conduct parallel histopathologic and mechanistic studies to advance colon cancer research.

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