Cell Traits in Colon Epithelium and Adenocarcinomas Bcl9/Bcl9l Are Critical for Wnt-Mediated Regulation of Stem

Canonical Wnt signaling plays a critical role in stem cell maintenance in epithelial homeostasis and carcinogenesis. Here, we show that in the mouse this role is critically mediated by Bcl9/Bcl9l, the mammalian homologues of Legless, which in Drosophila is required for Armadillo/beta-catenin signaling. Conditional ablation of Bcl9/Bcl9l in the intestinal epithelium, where the essential role of Wnt signaling in epithelial homeostasis and stem cell maintenance is well documented, resulted in decreased expression of intestinal stem cell markers and impaired regeneration of ulcerated colon epithelium. Adenocarcinomas with aberrant Wnt signaling arose with similar incidence in wild-type and mutant mice. However, transcriptional profiles were vastly different: Whereas wild-type tumors displayed characteristics of epithelial-mesenchymal transition (EMT) and stem cell-like properties, these properties were largely abrogated in mutant tumors. These findings reveal an essential role for Bcl9/Bcl9l in regulating a subset of Wnt target genes involved in controlling EMT and stem cell-related features and suggest that targeting the Bcl9/Bcl9l arm of Wnt signaling in Wnt-activated cancers might attenuate these traits, which are associated with tumor invasion, metastasis, and resistance to therapy. DOI: https://doi.org/10.1158/0008-5472.CAN-10-0148 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-35747 Accepted Version Originally published at: Deka, J; Wiedemann, N; Anderle, P; Murphy-Seiler, F; Bultinck, J; Eyckerman, S; Stehle, J C; André, S; Vilain, N; Zilian, O; Robine, S; Delorenzi, M; Basler, K; Aguet, M (2010). Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Research, 70(16):6619-6628. DOI: https://doi.org/10.1158/0008-5472.CAN-10-0148 Published OnlineFirst August 3, 2010. Cancer Res Jürgen Deka, Norbert Wiedemann, Pascale Anderle, et al. Cell Traits in Colon Epithelium and Adenocarcinomas Bcl9/Bcl9l Are Critical for Wnt-Mediated Regulation of Stem Updated Version 10.1158/0008-5472.CAN-10-0148 doi: Access the most recent version of this article at: Material Supplementary http://cancerres.aacrjournals.org/content/suppl/2010/08/05/0008-5472.CAN-10-0148.DC1.html Access the most recent supplemental material at: