B-Raf inhibitors induce epithelial differentiation in BRAF mutant colorectal cancer cells
Transcriptomics Dataset
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General Information
AccessionGSE50791
TitleB-Raf inhibitors induce epithelial differentiation in BRAF mutant colorectal cancer cells
DescriptionMutations in the BRAF proto-oncogene, which encodes the B-Raf kinase, are associated with more aggressive, less-differentiated and therapy-resistant colorectal cancers (CRC). However, the molecular mechanisms responsible for these correlations remain unknown. Here, we report the characterization of human isogenic CRC cell line models (Caco-2, HT29, Colo-205) in which we modulate the expression of the B-RafV600E oncoprotein either by conditional cDNA or shRNA expression. Using these models in conventional and three dimensional tissue culture systems, we demonstrate that genetic depletion of endogenous B-RafV600E decreases cellular motility and invasion, while it induces hallmarks of differentiated epithelia such as the formation of functional adherens and tight junctions. Importantly, these effects are recapitulated by exposing these lines to B-Raf (PLX4720, vemurafenib, dabrafenib) or MEK inhibitors (trametinib). Furthermore, loss of endogenous B-RafV600E in HT29 xenografts does not only stall tumor growth, but also induces epithelial structures with marked expression of Cdx-2, a prognostic marker and master regulator of intestinal morphogenesis. By performing the first transcriptome profiles of B-Raf inhibitor treated 3D cultures of a primary adenocarcinoma and a metastasis derived CRC cell line, we establish functional links between B-RafV600E and proteins of known and potentially new prognostic relevance. We propose that B-Raf/MEK/ERK pathway inhibitors could be used to induce CRC differentiation and thereby to limit metastatic disease.
Landing Pagehttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50791
RepositoryGene Expression Omnibus
Tools used to analyze the dataset
Keyword
Dataset Accession
Enrichr
Published May 2016
A comprehensive gene set enrichment analysis web server 2016 update
7759
65
Characteristic Direction
Published March 2014
A geometrical multivariate approach to identify differentially expressed genes
26829
L1000CDS2
Published August 2016
An ultra-fast LINCS L1000 Characteristic Direction signature search engine
7756
GeneMANIA
Published June 2010
Biological network integration for gene prioritization and predicting gene function
7435
PAEA
Published November 2015
Enrichment analysis tool implementing the principal angle method
3879
Canned Analyses generated with the dataset
Filters  
Dataset Accession
Tool Name
Direction
Cell Type
Geneset
Small molecules which mimic Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Small molecules which mimic Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Small molecules which mimic Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
Small molecules which reverse Plx4720 treatment
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which rev...
Enrichment analysis of genes dysregulated following Plx4720 treatment
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Enrichment analysis of genes dysregulated following Plx4720 treatment
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Enrichment analysis of genes dysregulated following Plx4720 treatment
PAEA, Characteristic Direction
An enrichment analysis was performed on the top most dyresgulated genes determined by appl...
Small molecules which mimic BRAF Drug
L1000CDS2, Characteristic Direction
The L1000 database was queried in order to identify small molecule perturbations which mim...
...
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