APC loss promotes intestinal transformation though B-CATENIN-independent dysregulation of a GSK3-AJUBA-YAP signaling axis

The majority of colorectal cancer (CRC) cases are believed to be initiated by the genetic inactivation of the APC tumor suppressor, which negatively regulates the Wnt effector beta-catenin. This has led to the prevailing view that loss of APC drives tumorigenesis through constitutive activation of the Wnt/beta-catenin pathway. Although activation of beta-catenin is necessary for tumor initiation, activating mutations in beta-catenin are rare in CRC. Instead, CRC typically exhibits poorly understood mechanisms that favor the genetic inactivation of APC over activating mutations in beta-catenin or other Wnt pathway components, which are more commonly seen in other types of carcinoma. In this study, we profiled single cells isolated from organoids with floxed alleles of Apc (Apc f/f), beta-catenin (beta-Catenin Exon3 f/f), or organoids expressing a dominant-negative form of Tcf4 with floxed alleles of Apc (Apc f/f). Overall design: Organoids were cultured for 24 hours before processing. Single cells were isolated from organoids with floxed alleles of Apc (Apc f/f), beta-catenin (beta-Catenin Exon3 f/f), or organoids expressing a dominant-negative form of Tcf4 with floxed alleles of Apc (Apc f/f).