Moor, Andreas E; Anderle, Pascale; Cantù, Claudio; Rodriguez, Patrick; Wiedemann, Norbert; Baruthio, Frédérique; Deka, Jürgen; André, Sylvie; Valenta, Tomas; Moor, Matthias B.; Győrffy, Balázs; Barras, David; Delorenzi, Mauro; Basler, Konrad; Aguet, Michel (2015). BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. EBioMedicine, 2(12), pp. 1932-1943. Elsevier 10.1016/j.ebiom.2015.10.030
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension |
UniBE Contributor: |
Moor, Matthias |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2352-3964 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Matthias Moor |
Date Deposited: |
08 Oct 2019 14:09 |
Last Modified: |
05 Dec 2022 15:30 |
Publisher DOI: |
10.1016/j.ebiom.2015.10.030 |
PubMed ID: |
26844272 |
Uncontrolled Keywords: |
BCL9/9L-β-catenin Cancer stem cells Colorectal cancer subtypes Patient outcome WNT signaling |
BORIS DOI: |
10.7892/boris.133428 |
URI: |
https://boris.unibe.ch/id/eprint/133428 |
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