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EBioMedicine. 2015 Oct 30;2(12):1932-43. doi: 10.1016/j.ebiom.2015.10.030. eCollection 2015 Dec.

BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.

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Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
MTA TTK Lendület Cancer Biomarker Research Group, 2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, CH-1066 Lausanne, Switzerland; Oncology Department, University of Lausanne, CH-1015 Lausanne, Switzerland.


BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.


BCL9/9L-β-catenin; Cancer stem cells; Colorectal cancer subtypes; Patient outcome; WNT signaling

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