Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Impact of ectopic expression of SNAIL2, ZEB2, ZEB1 or TWIST1 on BRAF-target genes in the murine melanocytic melan-a cell line

ABSTRACT: We have demonstrated that the oncogenic activation of B-RAF (using a truncated delta-BRAF-ER version inducible with tamoxifen) in the melan-a melanocyte cell line triggers the activation of Zeb1 and Twist1 at the expanse of Zeb2 and Snail2. Enforced maintenance of Zeb2 or Snail2 expression reduces the B-RAF oncogenic potential while ectopic expression of Zeb1 or Twist1 cooperates with B-RAF in melan-a cell transformation. To get an insight into the properties of these embryonic transcription factors, gene expression profiles of melan-a-derived cell lines either expressing a non-activated B-RAF (- tamoxifen) or an activated BRAF (+ tamoxifen) alone or in combination with Snail2, Zeb2, Twist1 or Zeb1 have been established. Melan-a cells were transduced with an activated version of BRAF(delta-BRAF-ER, inducible with tamoxifen) alone or in combination with SNAIL2, ZEB2, ZEB1 or TWIST1. Gene expression profiles before or following BRAF activation (alone or in combination with the embryonic transcription factors) were determined. Ectopic expression of SNAIL2, ZEB2, ZEB1 or TWIST1 on BRAF-target genes in the murine melanocytic melan-a cell line.

ORGANISM(S): Mus musculus

SUBMITTER: stéphane ansieau

PROVIDER: E-GEOD-39030 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma.

Caramel Julie J Papadogeorgakis Eftychios E Hill Louise L Browne Gareth J GJ Richard Geoffrey G Wierinckx Anne A Saldanha Gerald G Osborne Joy J Hutchinson Peter P Tse Gina G Lachuer Joël J Puisieux Alain A Pringle J Howard JH Ansieau Stéphane S Tulchinsky Eugene E

Cancer cell 20130926 4

Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BR ...[more]

PMID: 24075834

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Project description:Fifty percent of cutaneous melanomas are driven by activated BRAFV600E, but tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to MAPK pathway inhibition we identified the combination PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ERBB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720. To identify potential mechanisms of resistance to PLX4720 treatment and synergy with lapatinib treatment we performed a multi-platform functional genomics analysis to profile the genome as well as the transcriptional and proteomic responses of these cell lines to treatment with PLX4720. We found modest levels of resistance correlated with the zygosity of the BRAF V600E allele and RTK mutational status. Layered over base-line resistance was substantial upregulation of many ERBB pathway genes in response to BRaf inhibition, thus generating the vulnerability to combination with lapatinib. The transcriptional responses of ERBB pathway genes are associated with a number of transcription factors, including ETS2 and its associated cofactors that represent a convergent regulatory mechanism conferring synergistic drug susceptibility in the context of diverse mutational landscapes. 12 BRAF mutant melanomas and 4 melanomas with WT BRAF were exposed plx4720 treatment to evaluate their responses after 8 hours of treatment. 5 of the 12 BRAF mutant melanomas responses were also evaluated in response to the treatment of lapatinib alone, masitinib alone, the combination of lapatinib with plx4720, or the combination of masitinib with plx4720. All samples were run in at least triplicate.

Dataset Information

Impact of ectopic expression of SNAIL2, ZEB2, ZEB1 or TWIST1 on BRAF-target genes in the murine melanocytic melan-a cell line

Publications

A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma.

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