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Melanoma cell culture phenotypes

ABSTRACT: Recent trials with MAPK inhibitors have shown promising results in many patients with metastatic melanoma; however, nearly all responding patients experience disease relapse. We describe here how melanoma cells respond to MAPK inhibition in a phenotype-specific manner, suggesting that slow cycling invasive phenotype cells provide a treatment-resistant pool from which disease relapse may be derived. The implication is that while MAPK inhibition may successfully treat proliferating cells, another cell population needs to be addressed at the same time. 12 samples

ORGANISM(S): Homo sapiens

SUBMITTER: Daniel Widmer

PROVIDER: E-GEOD-28335 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status.

Zipser Marie C MC Eichhoff Ossia M OM Widmer Daniel S DS Schlegel Natalie C NC Schoenewolf Nicola L NL Stuart Darrin D Liu Weihua W Gardner Humphrey H Smith Paul D PD Nuciforo Paolo P Dummer Reinhard R Hoek Keith S KS

Pigment cell & melanoma research 20110112 2

Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irresp ...[more]

PMID: 21176117

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Melanoma cell culture phenotypes I

Project description:Recent trials with MAPK inhibitors have shown promising results in many patients with metastatic melanoma; however, nearly all responding patients experience disease relapse. We describe here how melanoma cells respond to MAPK inhibition in a phenotype-specific manner, suggesting that slow cycling invasive phenotype cells provide a treatment-resistant pool from which disease relapse may be derived. The implication is that while MAPK inhibition may successfully treat proliferating cells, another cell population needs to be addressed at the same time.

2011-04-05 | GSE28335 | GEO

Melanoma cell culture phenotypes II

Project description:These samples are part of a study that tries to find melanoma subgroups by the mean of gene expression analysis. Recent trials with MAPK inhibitors have shown promising results in many patients with metastatic melanoma; however, nearly all responding patients experience disease relapse. We describe here how melanoma cells respond to MAPK inhibition in a phenotype-specific manner, suggesting that slow cycling invasive phenotype cells provide a treatment-resistant pool from which disease relapse may be derived. The implication is that while MAPK inhibition may successfully treat proliferating cells, another cell population needs to be addressed at the same time.

2012-05-24 | GSE33727 | GEO

Melanoma cell culture phenotypes

Project description:This SuperSeries is composed of the following subset Series: GSE28335: Melanoma cell culture phenotypes I GSE33727: Melanoma cell culture phenotypes II Refer to individual Series

2011-11-17 | E-GEOD-33728 | biostudies-arrayexpress

Combinatorial treatment with PARP and MAPK inhibitors overcomes phenotype switch-driven drug resistance in advanced melanoma

Project description:Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors. A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of melanoma patients. Using a drug screen targeting chromatin regulators in patient-derived 3D MAPK inhibitor-resistant melanoma cell cultures, we discovered that PARP inhibitors restore sensitivity to MAPK inhibitors, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARP inhibitors induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed EMT-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPK inhibitor-sensitive state. The combination of PARP and MAPK inhibitors synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating melanoma patients with PARP inhibitors in combination with MAPK inhibitors to abrogate acquired therapy resistance.

2023-08-24 | GSE221241 | GEO

Genome-wide maps of transcriptomic and epigenomic state in melanoma cell lines

Project description:A mechanistic relationship between tumor epigenetic plasticity and nongenetic adaptive resistance to therapy is described, with MAPK inhibition of BRAF-mutant melanoma cells providing the model system. Upon inhibition, these largely melanocytic cells undergo reversible cell-state changes, ultimately yielding a drug-resistant mesenchymal-like phenotype. Epigenomic and transcriptomic kinetic studies, coupled with information theory and dynamic system modeling, revealed that, after just 3-days of treatment, RelA drives chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. Specifically, RelA transcriptionally inhibits SOX10 and NFKBIE through recruiting KDM5B and HDAC1 to down-regulate histone marks H3K4me3 and H3K27ac at their promoter regions. Suppression of SOX10 mediates melanoma regression towards drug-refractory phenotypes. These findings were confirmed in melanoma patients under MAPK inhibitor treatment, providing mechanistic insights into resistance-leading epigenetic reprogramming triggered following drug exposure.

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The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma [ChIP-seq]

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.

2024-02-22 | GSE254701 | GEO

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

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Melanoma cell lines treated with dabrafenib ± trametinib

Project description:Rapid resistance to BRAF inhibitors in BRAFV600-mutant metastatic melanoma has produced an urgent need for new treatment options. BRAF inhibitor resistance commonly involves reactivation of mitogen-activated protein kinase (MAPK) signaling and yet inhibition of downstream kinases has not circumvented resistance, partly because MAPK is regulated via a complex network of feedback mechanisms that influence pathway rebound. To examine the transcriptome responses of melanoma cells to MAPK inhibition, a panel of 11 BRAFV600-mutant melanoma cell lines were treated with control (DMSO), 100nM dabrafenib alone (i.e BRAF inhibitor monotherapy) or 100nM dabrafenib + 10nM trametinib (i.e combination BRAF + MEK inhibition) for 24h.

2017-09-20 | GSE98314 | GEO

The effect of MEK inhibition on transcription in melanoma [Batch 1]

Project description:In order to reveal the downstream targets of MAPK in melanoma, we measured the expression of 12 melanoma cell lines pre and post MEK inhibition Samples were treated with 50nM of the MEK inhibitor PD901 and collected 8 hours after treatment

2015-01-01 | E-GEOD-51051 | biostudies-arrayexpress

Project description:MAPK inhibition in BRAFV600 mutant melanoma patient derived xenografts

| PRJNA562481 | ENA

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