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Series GSE60837 Query DataSets for GSE60837
Status Public on Nov 08, 2015
Title BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome.
Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome.
Overall design Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
Web link http://doi:10.1016/j.ebiom.2015.10.030
Contributor(s) Moor AE, Anderle P, Cantù C, Valenta T, Wiedemann N, Baruthio F, Rodriguez P, Deka J, André S, Györffy B, Delorenzi M, Basler K, Aguet M
Citation(s) 26844272
Submission date Aug 27, 2014
Last update date May 15, 2019
Contact name Andreas Moor
Organization name ETH Zurich
Department Department of Biosystems Science and Engineering
Street address Mattenstrasse 26
City Basel
ZIP/Postal code 4058
Country Switzerland
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (25)
GSM1489672 AOM-DSS Bcl9/9l-KO tumor 1
GSM1489673 AOM-DSS Bcl9/9l-KO tumor 2
GSM1489674 AOM-DSS Bcl9/9l-KO tumor 3
BioProject PRJNA259648
SRA SRP045828

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE60837_RAW.tar 4.6 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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