Wildtype C-Raf gene dosage and dimerization drive prostate cancer metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235178 | GEO | 2024/01/02
REPOSITORIES: GEO
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Project description:Wildtype C-Raf gene dosage and dimerization drive prostate cancer metastasis
| PRJNA984718 | ENA
Project description:Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway. A role for non-mutated Raf in metastasis is also emerging, but the key mechanisms remain unclear. Elevated expression of any of the three wild-type Raf family members (C, A, or B) can drive metastasis. We utilized an in vivo model to show that wild-type C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage-dependent manner. Analysis of the transcriptomic and phosphoproteomic landscape indicated that C-Raf-driven metastasis is accompanied by upregulated MAPK signaling. Use of C-Raf mutants demonstrated that the dimerization domain, but not its kinase activity, is essential for metastasis. Endogenous Raf monomer knockouts revealed that C-Raf's ability to form dimers with endogenous Raf molecules is important for promoting metastasis. These data identify wild-type C-Raf heterodimer signaling as a potential target for treating metastatic disease.
| S-EPMC10711388 | biostudies-literature
Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)). Cell lines growing in culture (n=5) were treated with the RAF inhibitor PLX4032 (250nM or 1000nM) or vehicle alone (0.1% DMSO) as control, for eight hours.
2010-07-18 | E-GEOD-20051 | biostudies-arrayexpress
Project description: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.
2014-12-21 | GSE50791 | GEO
Project description: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. To measure the time resolved gene responses, RNA was isolated from PLX4720 or DMSO treated Colo-205 and HT29 3D culture cell lysates at days 1,3 and 10 and days 1,3, and 8, respectively. The time points for HT29 cells were taken in biological duplicates.
2014-12-21 | E-GEOD-50791 | biostudies-arrayexpress
Project description:In this study 14 different RAF, MEK, or ERK inhibitors were tested in ASPC1 and PANC1 PDA cell lines
2024-04-28 | GSE252002 | GEO
Project description:To understand the transcriptional impact of FOXD3 in melanoma cells, we utilized a microarray approach. We collected RNA from three unrelated mutant B-RAF melanoma cell lines (WM115, WM793, and A375) that were engineered to inducibly express FOXD3 or the control gene, ?-galactosidase (LacZ), after 5 days of transgene induction. This time point was chosen based on maximal phenotypic changes previously observed. Comparison of gene signatures between the 3 cell lines produced approximately 2,600 common genes differentially regulated by FOXD3-expressing cells compared to the LacZ controls. Three unrelated mutant B-RAF melanoma cell lines (WM115, WM793, and A375) were induced to express FOXD3 and compared against the same cell lines expressing the control gene, ?-galactosidase (LacZ).
2013-03-31 | E-GEOD-43962 | biostudies-arrayexpress
Project description:Melanocyte are melanin-producing cells located in the bottom layer of the skin's epidermis and in the hair follicle. Melanin is the pigment primarily responsible notably for skin and hair color. Our team had previously shown a role for B-raf and C-raf genes in the maintenance of melanocyte stem cells located in mice hair follicle (Valluet et al, 2012). The aim of the present project was to understand the role of B-RAF and C-RAF kinases in melanocyte stem cell self-renewal. To reach this goal, we have generated a new mouse model in which cells of the melanocyte lineage can be followed by GFP expression. We performed gene array on melanocyte stem cell B-raf+/+; C-raf+/+ and B-raf-/-; C-raf-/-in order to identify the RAF kinases target genes which are involved in melanocyte stem cell self-renewal. Moreover, to better characterize the melanocyte stem cell population, we compared its gene expression profile to the melanoblast one (melanocyte stem cell's progenitors).
2019-09-02 | GSE86385 | GEO
Project description:SChLAP1 is a novel long non-coding RNA expressed in prostate cancer. Here we performed transcriptional profiling of the benign immortalized prostate cell line RWPE overexpressing two isoforms of the SChLAP-1 lncRNA compared with RWPE overexpressing LACZ. Our goal was to determine the effect of SChLAP1 overexpression on gene expression in prostate cells. Two-condition experiment: RWPE overexpressing SChLAP1 versus RWPE overexpressing LACZ. Biological replicates: 1 control replicate, 2 experimental replicates. Technical replicates: 2 replicates per SChLAP1 isoform. Cell lines: RWPE.
2013-07-20 | E-GEOD-40385 | biostudies-arrayexpress
Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)).
2010-07-18 | GSE20051 | GEO