A Gatekeeper Function for p120 and the E-cadherin Complex in Intestinal Tumorigenesis

Abstract

E-cadherin is widely recognized as a tumor- and/or metastasis suppressor, with its activity as a cell-cell adhesion receptor is dependent on tightly coupled interactions with cytoplasmic cofactors p120-, α-, and β-catenins. However, how the catenins, particularly p120, influence tumor initiation and metastasis is not clearly established. Here, we use conditional p120 ablation along with the Apc1638 and ApcMin mouse models to directly examine the role of p120 in intestinal tumorigenesis. Surprisingly, limited p120 knockout in less than 10% of the intestinal epithelium increased tumor development by up to 10-fold. The tumors, however, did not exhibit the expected complete loss of p120 and were found instead to be monoallelic, suggesting that p120 functions as a haploinsufficient tumor suppressor. Indeed, further studies show loss of one p120 allele is sufficient to induce the changes observed in total tumor number and that these results were not due to interaction with p120’s nuclear binding partner, Kaiso. Surprisingly, retention of the remaining p120 allele was evidently obligatory in adenomatous cells, as complete loss of p120 was selectively incompatible with tumor cell viability. To better appreciate the impact of p120 haploinsufficiency, we turned to a Sleeping Beauty mutagenesis system that enables semi-quantitative analyses of relative tumorigenic potency through mutation frequency. Surprisingly, p120 and α-catenin are among the highest ranked genes in this system, with E-cadherin close behind. Remarkably, p120, α-catenin, and E-cadherin all ranked within the top 4% of 919 identified mutations in the Apc-sensitized intestine. As loss of any of these three components destabilized the cadherin complex, monoallelic disruption at any of these loci likely impacts functionality and accelerates tumorigenesis. Thus, although E-cadherin is widely recognized as a metastasis suppressor in colorectal cancer, our data show that the integrity of the cadherin complex is critical at the earliest stages of tumor initiation and progression.