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SOFT file
| Title / Description |
B-Raf inhibitors induce epithelial differentiation in BRAF mutant colorectal cancer cells |
| Accession |
GSE50791
|
| Summary |
Mutations 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. |
| Organism |
Homo sapiens |
| Platform |
GPL10558 |
| Normalized |
False |
| Parsed SOFT file |
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Metadata
| Differential expression method |
Characteristic Direction
|
| Cutoff |
500 |
| Drug_name |
PLX4720 |
| Smiles |
CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=NC=C(C=C23)Cl)F |
| Pubchem_cid |
24180719 |
| Cell_type |
HT29 3D culture cell - Day 1 |
| Organism |
human |
Visualizations
| Principal Component Analysis |
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| Hierarchical clustering |
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External Links and Downloads
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Gene lists
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Enrichr
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L1000CDS2
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PAEA
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