Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/β-catenin signaling

Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β- cateninshRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β- cateninsignaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β- catenininhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β- cateninpathway colorectal cancer cells resumed proliferation and reacquired a cryptprogenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β- catenincorrelated with cryptprogenitor but not differentiation markers, suggesting that the Wnt/β- cateninpathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β- cateninpathway.