title: BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.
abstract: 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.
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Andreas E
authors: AE
authors: Moor
authors: SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors: Pascale
authors: P
authors: Anderle
authors: Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
authors: Claudio
authors: C
authors: Cantù
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Patrick
authors: P
authors: Rodriguez
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Norbert
authors: N
authors: Wiedemann
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Frédérique
authors: F
authors: Baruthio
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Jürgen
authors: J
authors: Deka
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Sylvie
authors: S
authors: André
authors: Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
authors: Tomas
authors: T
authors: Valenta
authors: Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors: Matthias B
authors: MB
authors: Moor
authors: MTA TTK Lendület Cancer Biomarker Research Group, 2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
authors: Balázs
authors: B
authors: Győrffy
authors: SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
authors: David
authors: D
authors: Barras
authors: 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.
authors: Mauro
authors: M
authors: Delorenzi
authors: Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
authors: Konrad
authors: K
authors: Basler
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors: Michel
authors: M
authors: Aguet
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D066264:Datasets as Topic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors; D059467:Transcriptome; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C111180:BCL9 protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors; D051176:beta Catenin
keywords: BCL9/9L-β-catenin; Cancer stem cells; Colorectal cancer subtypes; Patient outcome; WNT signaling