Dissecting the Cooperation between oncogenic KRAS, oncogenic beta-Catenin and the WNT-Pathway in Intestinal Tumorigenesis (#48)
Activation of the canonical WNT pathway occurs in the vast majority of colorectal cancers. However, the severity and outcome of the disease strongly varies from patient to patient, even within one particular tumor stage. This heterogeneity is governed in large parts by the individual tumor genetics, i.e., the combination of oncogenic mutations. To dissect the contribution of the level of WNT-pathway activation to intestinal tumorigenesis, we have analyzed a series of newly established genetic mouse models. First, the oncogene β-catenin (Ctnnb1) with an aminoterminal deletion of 131 amino acids (DN-Bcat) has been introduced into the A33 gene locus, leading to specific expression of oncogenic β-catenin in intestinal epithelia. The A33(DN-Bcat) mouse recapitulates a relatively weak level of Wnt activation, which was nonetheless sufficient to shift the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Aberrant crypt formation and spontaneous tumorigenesis were induced, albeit with low incidences of 50% and 37%, respectively. Interestingly, only a specific subset of Wnt target genes, including MMP7 and Tenascin-C, was differentially up-regulated in pre-malignant tissue, indicating a major role for early tumor development. In accordance, we detected highest expression of MMP7 in benign adenomas and in early tumor stages in a series of human colorectal tumors (n=51). Moreover, the mutant intestinal epithelium was sensitive towards Wnt induced tumorigenesis as evidenced by an increase of intestinal polyposis in both mutagen-induced (AOM) and two different genetic (Apcmin/+ and Apc1638N/+ ) mouse models of intestinal cancer. In contrast, a genetic model combining the A33(DN-Bcat) mutation with a oncogenic KrasG12V transgene showed a merely additive phenotype, as compared to single mutant littermates. We propose a mechanism whereby oncogenic b-catenin cooperates with mutant Apc to induce transcriptional changes which promote a pro-angiogenic tumor microenvironment and results in increased tumourigenesis.