An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents

Area of Science:

• Genetics and Molecular Biology
• Cancer Research
• Animal Models

Background:

• Mutations in the DNA mismatch repair (MMR) gene MSH2 are linked to Lynch syndromes and sporadic colorectal cancers.
• Msh2-deficient mice typically develop lymphoma, not accurately modeling colorectal cancer phenotypes.

Purpose of the Study:

• To create and examine mice with tissue-specific Msh2 gene inactivation for improved colorectal cancer modeling.
• To evaluate the efficacy of chemotherapy in these novel mouse models.

Main Methods:

• Generated conditional Msh2 knockout mice (Msh2(LoxP)) with tissue-specific Cre recombinase expression (EIIa-Cre and Villin-Cre).
• Created allelic phase mutants by combining Msh2(LoxP) with null or specific mutation alleles.
• Treated mice with cisplatin or FOLFOX chemotherapy and monitored tumor growth using MRI.

Main Results:

• Villin-Cre mediated Msh2 deletion specifically in intestinal epithelial cells, leading to MMR deficiency and microsatellite instability.
• Tumors in these mice exhibited somatic mutations in the Apc gene, characteristic of colorectal cancer.
• Msh2(LoxP/G674D) mice showed reduced tumor size and sustained apoptosis in response to FOLFOX, unlike Msh2(LoxP/null) mice.

Conclusions:

• Msh2(LoxP/LoxP) mice with specific Cre transgenes serve as effective preclinical models for Lynch syndrome and MMR-deficient colorectal cancers.
• These models are valuable for evaluating drug efficacy in MMR-deficient tumor contexts.
• The study highlights the potential for developing targeted therapies for MSH2-associated cancers.