Loss of p120ctn causes EGFR-targeted therapy resistance and failure.

Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While targeted EGFR therapy is initially effective in 75% of patients, a majority of patients relapse within the first year due to poorly understood mechanisms of resistance. p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy. In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer. Furthermore, p120ctn down-regulation synergizes with EGFR overexpression to cause a highly invasive cell phenotype. The purpose of this present study was to investigate whether p120ctn down-regulation induced EGFR therapeutic resistance. Using human esophageal keratinocytes, we have found that EGFR-targeting compounds are toxic to cells overexpressing EGFR. Interestingly, these therapies do not cause toxicity in cells with EGFR overexpression and decreased p120ctn expression. These data suggest that decreased p120ctn causes resistance to EGFR therapy. We believe these findings are of utmost importance, as there is an unmet need to discover mechanisms of EGFR resistance.

Adenoma formation following limited ablation of p120-catenin in the mouse intestine.

p120 loss destabilizes E-cadherin and could therefore result in tumor and/or metastasis-promoting activities similar to those caused by E-cadherin downregulation. Previously, we reported that p120 is essential in the intestine for barrier function, epithelial homeostasis and survival. Conditional p120 ablation in the mouse intestine induced severe inflammatory bowel disease, but long-term cancer-related studies were impossible because none of the animals survived longer than 21 days. Here, we used a tamoxifen-inducible mouse model (Vil-Cre-ER(T2);p120(fl/fl)) to limit the extent of p120 ablation and thereby enable long-term studies. Reducing p120 KO to ∼10% of the intestinal epithelium produced long-lived animals outwardly indistinguishable from controls. Effects of prolonged p120 absence were then evaluated at intervals spanning 2 to 18 months. At all time points, immunostaining revealed microdomains of p120-null epithelium interspersed with normal epithelium. Thus, stochastic p120 ablation is compatible with crypt progenitor cell function and permitted lifelong renewal of the p120-null cells. Consistent with previous observations, a barrier defect and frequent infiltration of neutrophils was observed, suggesting that focal p120 loss generates a microenvironment disposed to chronic inflammation. We report that 45% of these animals developed tumors within 18 months of tamoxifen induction. Interestingly, ß-catenin was upregulated in the majority, but none of the tumors were p120 null. Although further work is required to directly establish mechanism, we conclude that limited p120 ablation can promote tumorigenesis by an indirect non-cell autonomous mechanism. Given that byproducts of inflammation are known to be highly mutagenic, we suggest that tumorigenesis in this model is ultimately driven by the lifelong inability to heal chronic wounds and the substantially increased rates of stochastic gene mutation in tissue microenvironments subjected to chronic inflammation. Indeed, although technical issues precluded direct identification of mutations, ß-catenin upregulation in human colon cancer almost invariably reflects mutations in APC and/or ß-catenin.

p120 catenin is required for normal renal tubulogenesis and glomerulogenesis.

Defects in the development or maintenance of tubule diameter correlate with polycystic kidney disease. Here, we report that absence of the cadherin regulator p120 catenin (p120ctn) from the renal mesenchyme prior to tubule formation leads to decreased cadherin levels with abnormal morphologies of early tubule structures and developing glomeruli. In addition, mutant mice develop cystic kidney disease, with markedly increased tubule diameter and cellular proliferation, and detached luminal cells only in proximal tubules. The p120ctn homolog Arvcf is specifically absent from embryonic proximal tubules, consistent with the specificity of the proximal tubular phenotype. p120ctn knockdown in renal epithelial cells in 3D culture results in a similar cystic phenotype with reduced levels of E-cadherin and active RhoA. We find that E-cadherin knockdown, but not RhoA inhibition, phenocopies p120ctn knockdown. Taken together, our data show that p120ctn is required for early tubule and glomerular morphogenesis, as well as control of luminal diameter, probably through regulation of cadherins.

Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene.

p120-catenin (p120ctn) interacts with E-cadherin, but to our knowledge, no formal proof that p120ctn functions as a bona fide tumor suppressor gene has emerged to date. We report herein that p120ctn loss leads to tumor development in mice. We have generated a conditional knockout model of p120ctn whereby mice develop preneoplastic and neoplastic lesions in the oral cavity, esophagus, and squamous forestomach. Tumor-derived cells secrete granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNFα). The tumors contain significant desmoplasia and immune cell infiltration. Immature myeloid cells comprise a significant percentage of the immune cells present and likely participate in fostering a favorable tumor microenvironment, including the activation of fibroblasts.