Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA404058 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6025320_1.fastq.gz | Fastqsanger.gz | |||
| SRR6025320_2.fastq.gz | Fastqsanger.gz | |||
| SRR6025321_1.fastq.gz | Fastqsanger.gz | |||
| SRR6025321_2.fastq.gz | Fastqsanger.gz | |||
| SRR6025314_1.fastq.gz | Fastqsanger.gz |
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Project description:Expression changes in melanoma cell lines under BRAFi treatment timepoints [RNA-Seq.CellLine.batch4]
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Project description:Parental vs. BRAFi Resistant Melanoma Cell Lines
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Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi. Expression of WNT5A-correlated genes was compared in melanoma cell lines generated to be resistant to PLX4032 and the their associated naïve parental line Basal expression of the WNT5A-correlated genes was also measured in experiments comparing each naïve line to a mixed reference pool containing equal amounts of 47 melanoma cell lines.
2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress
Project description:Tumor-associated stromal cells can enable cancer cells to become insensitive to therapy. They can promote aggressive phenotype in cancer cells, which become less responsive to drugs such as BRAF inhibitors (BRAFi) used to treat melanomas. To clarify potential mechanism behind stromal influence on melanoma, we analyzed gene expression in Melmet 5 melanoma cells grown as mono-cultures or co-cultures with lung fibroblasts with/without BRAFi. We have shown that Melmet 5 growing as co-cultures gained a de-differentiated, invasive transcriptional state, which is known to be linked to BRAFi-resistance. The transcriptional changes induced by BRAFi were much larger in Melmet 5 mono-cultures compared to co-cultures, indicating a much dampened transcriptional response to BRAFi in melanoma under the influence of fibroblasts. We conclude that interaction with the stromal cells stimulate melanoma cell transition to the invasive de-differentiated phenotype, leading to a worse response to BRAF inhibitors. Total RNA was isolated from Melmet 5 cell line growing as mono- or co-cultures with fibroblasts for 72 hours and treated with BRAFi for the last 24 hours.
2015-08-01 | E-GEOD-67637 | biostudies-arrayexpress
Project description:Purpose: To identify new targets in melanoma for targeted treatment based on a mutational analysis of melanoma cell lines and subsequent individualized treatment combinations. Experimental Design: A series of 57 melanoma cell lines (mostly short-term cultures) are analyzed for their mutation pattern based on a mutation panel of 83 genes selected from the most abundant mutations (more than 5 % of samples). Of these, 28 cell lines are treated with small molecule inhibitors either as single-agent or combination therapy. Most effective therapies are estimated by Chou Talaley method, applied to multiple drug treatments, based on growth characteristics of melanoma cells during life-cell imaging. Results: In a number of cell lines, combination treatment showed better treatment response rates than monotherapy. BRAFi and an inhibitor of a further pathway is more efficient to induce an anti-proliferative effect than the standard therapy with a BRAFi-MEKi combination. Among these are PI3K/mTOR inhibitor apitolisib either together with a BRAFi or as triple combination with BRAFi/MEKi. A combination of BRAFi and CDK4/6 inhibitor palbociclib also showed significant synergy. The most promising drug combinations in NRASmut cell lines is a triple combination of MEKi, ERKi and and PI3K/mTOR apitolisib, or a combination of MEKi, apitolisib and aurora A kinase inhibitor alisertib. Transcriptomic analysis showed that BRAF and NRAS mutant cell lines could be differentiated by ARHGAP42 and DLD expression, both higher expressed in BRAFmut cell lines, and ARHGAP42 being a putative new target for BRAFmut melanoma cells. Conclusion: Combination treatment of melanoma cells with individual drug combinations based on mutational patterns are sometimes more effective than monotherapy or classical double-agent therapy and may thereby replace classical treatment approaches.
2025-01-24 | GSE287916 | GEO
Project description:Expression changes in melanoma cell lines pre MAPKi treatment vs. post-MAPKi resistance (RNA-seq_CellLine.batch2)
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Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi.
2014-03-06 | GSE55583 | GEO
Project description:Tumor-associated stromal cells can enable cancer cells to become insensitive to therapy. They can promote aggressive phenotype in cancer cells, which become less responsive to drugs such as BRAF inhibitors (BRAFi) used to treat melanomas. To clarify potential mechanism behind stromal influence on melanoma, we analyzed gene expression in Melmet 5 melanoma cells grown as mono-cultures or co-cultures with lung fibroblasts with/without BRAFi. We have shown that Melmet 5 growing as co-cultures gained a de-differentiated, invasive transcriptional state, which is known to be linked to BRAFi-resistance. The transcriptional changes induced by BRAFi were much larger in Melmet 5 mono-cultures compared to co-cultures, indicating a much dampened transcriptional response to BRAFi in melanoma under the influence of fibroblasts. We conclude that interaction with the stromal cells stimulate melanoma cell transition to the invasive de-differentiated phenotype, leading to a worse response to BRAF inhibitors.
2015-08-01 | GSE67637 | GEO
Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.
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