The inducible KPC:APC mouse organoid model for colon carcinogenesis studies

authors

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

keywords

• KPCAPC
• Colon organoid
• Carcinogenesis

abstract

Apcmin mouse is a widely used model of colorectal cancer, but inducible models are more suitable for colon carcinogenesis studies. 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. However, no corresponding in vitro model existed before. We developed the KPC:APC ex vivo inducible colorectal cancer organoid model to study cellular and molecular pathways involved in Apc-Kras-driven colon carcinogenesis. After generating the KPC:APC organoids in Matrigel, the mutations were induced with 4-OHT. The treatment efficiency was assessed by morphological and molecular analysis. Results showed no dose dependent effect and a better homogeneity when the organoids were treated 2 days after seeding. Morphological and molecular analysis showed that the carcinogenesis was efficiently induced by adding 0,125µL of 4-OHT for 24h in the medium. The validation of the KPC:APC organoid model will allow investigations on the effects of stressors (such as medical diagnostic exposures to low dose radiation) on colon carcinogenesis. The establishment of this ex vivo model combined with the KPC:APC mouse model will also provide the opportunity to conduct parallel histopathologic and mechanistic studies to advance colon cancer research.

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