BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.
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State: Public
Version: author
State: Public
Version: author
Serval ID
serval:BIB_CF71D7FE666E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.
Journal
Ebiomedicine
ISSN
2352-3964 (Electronic)
ISSN-L
2352-3964
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
2
Number
12
Pages
1932-1943
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
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.
Keywords
Animals, Cell Transformation, Neoplastic/genetics, Cell Transformation, Neoplastic/metabolism, Cluster Analysis, Colorectal Neoplasms/genetics, Colorectal Neoplasms/metabolism, Datasets as Topic, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Mice, Mice, Knockout, Neoplasm Proteins/antagonists & inhibitors, Neoplasm Proteins/genetics, Neoplastic Stem Cells/metabolism, Phenotype, Prognosis, Sequence Deletion, Signal Transduction, Transcriptome, beta Catenin/antagonists & inhibitors, beta Catenin/genetics
Pubmed
Web of science
Open Access
Yes
Create date
20/02/2016 16:55
Last modification date
17/09/2020 9:22