# A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations

## TL;DR

A mouse model with a specific β-catenin mutation mimics human colon cancer progression by promoting tumor formation and inflammation in the intestine.

## Contribution

The study introduces a novel mouse model with a hypermorphic β-catenin mutation that better replicates human sporadic colon cancer characteristics.

## Key findings

- gpA33ΔN-Bcat mice develop aberrant crypt foci and adenomatous polyps at frequencies similar to human sporadic colon cancer.
- Wnt target genes like MMP7 and Tenascin-C are upregulated in pre-malignant tissue, resembling early human tumor stages.
- The mutation leads to increased intestinal permeability and chronic inflammation, enhancing susceptibility to tumorigenesis.

## Abstract

Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great extent by the genetic make-up of individual tumors and the combination of oncogenic mutations. In order to express throughout the intestinal epithelium a degradation-resistant β-catenin (Ctnnb1), which lacks the first 131 amino acids, we inserted an epitope-tagged ΔN(1-131)-β-catenin-encoding cDNA as a knock-in transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33ΔN-Bcat mice showed an increase in the constitutive Wnt/β-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33ΔN-Bcat mice spontaneously developed aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to those observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7  and Tenascin-C, which are most highly expressed in benign human adenomas and early tumor stages, were upregulated in pre-malignant tissue of gpA33ΔN-Bcat mice, but those Wnt target genes associated with excessive proliferation (i.e. Cdnn1, myc) were not. We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33ΔN-Bcat mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of ΔN(1-131)-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.

Summary: The gpA33ΔN-Bcat mice provide a model that better mimics some aspects of sporadic colon cancer induction in humans in terms of tumor multiplicity and latency and site-specific (i.e. colon) tumor occurrence that coincides with upregulation of markers for human colorectal cancer progression.