Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas.
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.
Deka
Jürgen
J
Swiss Institute for Experimental Cancer Research, Swiss National Center of Competence in Research Molecular Oncology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Wiedemann
Norbert
N
Anderle
Pascale
P
Murphy-Seiler
Fabienne
F
Bultinck
Jennyfer
J
Eyckerman
Sven
S
Stehle
Jean-Christophe
JC
André
Sylvie
S
Vilain
Nathalie
N
Zilian
Olav
O
Robine
Sylvie
S
Delorenzi
Mauro
M
Basler
Konrad
K
Aguet
Michel
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D014157:Transcription Factors; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
C545436:BCL9 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D051153:Wnt Proteins