LncRNA related studies in MAPK-driven melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197623 | GEO | 2022/05/01
REPOSITORIES: GEO
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Project description:lncRNA related studies in MAPK-driven melanoma
| PRJNA811229 | ENA
Project description:Activating mutations in NRAS account for 20-30% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.
2024-09-20 | PXD046277 | Pride
Project description:Activating mutations in NRAS account for 15-20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.
2024-09-19 | PXD051431 | Pride
Project description:Purpose: Tumor radioresistance can be driven by ERK phosphorylation and its downstream targets. In this context, melanomas harboring constitutive MAPK/ERK activation have been considered for targeted radionuclide therapy (TRT) with a radiolabeled melanin tracer ([131I]ICF01012), alone or in combination with MEK inhibitors (MEKi). Experimental design: We used three dimensional (3D) melanoma spheroid models to evaluate the effects of TRT in combination with MEKi, in human BRAFV600E SK-MEL-3, NRASQ61K 1007 and WT B16F10 murine melanomas. TRT was assessed in vivo using the syngeneic model C57Bl5/NRAS 1007 for biodistribution, dosimetry, efficiency and molecular mechanisms. Results: In spheroids, TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant models that were resistant to TRT-induced apoptosis. However NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. Actually, mice bearing NRAS1007 melanoma and receiving 18.5MBq of [131I]ICF01012 had a significant extended survival (median: 92 vs 44 days, p < 0.0001), associated with a 93 Gy tumor deposit, leading to a dramatic decrease of tumor growth. Furthermore, the number of lymph node metastases was reduced in mice receiving [131I]ICF01012. Comparative transcriptomic analyses confirm a decrease of mitosis, proliferation and metastasis signature in TRT-treated tumors vs control tumors. These analyses also suggest that in this NRAS-melanoma, TRT acts through an increase of oxidation and inflammation as well as P53 activation. Conclusions: Our data support the view that combining [131I]ICF01012-TRT with MEKi can be of benefit for the treatment of advanced pigmented BRAF-mutant melanoma. Likewise, [131I]ICF01012 alone can be considered as a new potential NRAS-mutant melanoma treatment.
2021-03-31 | GSE162536 | GEO
Project description:In order to improve our understanding of microRNA (miRNA) deregulation in melanoma development and possible consequences for patient survival, miRNA expression profiles were determined, using an array based approach, in melanoma tumors, melanoma cell lines and normal melanocytes. Differentially expressed miRNAs were evaluated in relation to clinical characteristics, patient prognosis in terms of melanoma-specific survival, and mutational status for BRAF and NRAS.
2010-04-21 | GSE19387 | GEO
Project description:Despite the advent of immune-oncological therapies, patients with advanced NRAS-mutant melanoma still have a significantly worse prognosis than their BRAF-mutant counterparts. This is mainly due to a high propensity for resistance to available therapies targeting the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (MAPKi). Preclinical studies and mouse models have implicated the stress-activated MEK5/ERK5 MAPK cascade as a major resistance pathway activated by MAPKi-based targeted therapy in NRAS-mutant melanoma. Accordingly, MAPKi/ERK5i co-inhibition was capable of triggering a sustained cell cycle arrest in NRAS-mutant melanoma cells, but the key mediator(s) of its vigorous anti-proliferative effect remain elusive. Here, we further investigated the mechanism of MAPKi/ERK5i-induced cell cycle arrest in NRAS-mutant melanoma cells using both genetic methods and pharmacological inhibitors. Transcriptome analysis of human NRAS-mutant melanoma cells established that MAPKi/ERK5i-induced a near-complete shutdown of the mitotic machinery as consequence of a sustained G1 cell cycle arrest. This arrest was not only observed in diverse treatment-naïve melanoma cells but could also be induced in cells that already had developed resistance to therapeutic MEK inhibition (MEKi) and was accompanied by suppression of Cyclin D1 and E2F-mediated gene expression. Forced expression of Cyclin D1 and its effector kinase CDK4 restored cell cycle progression and mitotic gene expression in NRAS-mutant melanoma cells exposed to MEKi/ERK5i, implying Cyclin D/CDK4 activity as major target of combined MEKi/ERK5i. These findings suggest Cyclin D/CDK4 dependency as a major vulnerability of NRAS-mutant melanoma that could effectively be targeted by combined MAPKi/ERK5i.
2025-09-01 | GSE300191 | GEO
Project description:PREX2 truncating mutations occur in melanoma. We used microarray based gene expression profiling to compare expression patterns between xenografts harboring control GFP, wt PREX2 or various human relevant PREX2 mutants Primary xenograft tumors derived from primary immortalized melanocytes expressing indicated constructs were grown in ncr-nude mice and tumors harvested before before reaching 1.5cm size
2016-04-06 | E-GEOD-57309 | biostudies-arrayexpress
Project description:In order to improve our understanding of microRNA (miRNA) deregulation in melanoma development and possible consequences for patient survival, miRNA expression profiles were determined, using an array based approach, in melanoma tumors, melanoma cell lines and normal melanocytes. Differentially expressed miRNAs were evaluated in relation to clinical characteristics, patient prognosis in terms of melanoma-specific survival, and mutational status for BRAF and NRAS. Agilent microarray platform containing 470 miRNAs was used to determine miRNA expression profiles in 3 normal melanocytes (as non-neoplastic control), 21 melanoma cell lines and 16 clinical samples from fresh frozen regional lymph node metastases. To validate the microarray platform, the expression levels of some miRNAs were evaluated using RT-PCR and the correlation between the two platforms was assessed using Pearson Correlation analysis. The results obtained were further verified and confirmed by RT-PCR in an independent set of melanoma samples. Association between deregulated miRNAs and survival was determined by Univariate Cox proportional hazards model and log rank test.
2010-04-21 | E-GEOD-19387 | biostudies-arrayexpress
Project description:The tumor suppressive miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. Here we investigated whether oncogenic MAPK hyperactivation regulates miR-29 abundance and how this signaling axis impacts melanoma development. Using mouse embryonic fibroblasts and human melanocytes, we found that oncogenic MAPK signaling stimulates p53-independent and p53-dependent transcription of pri-miR-29b1~a and pri-miR-29b2~c, respectively. Expression analyses revealed that while pri-miR-29a~b1 remains elevated, pri-miR-29b2~c levels decrease during melanoma progression. Using a rapid mouse modeling platform, we showed that inactivation of miR-29 in vivo accelerates the development of frank melanomas and decreases overall survival. We identified MAFG as a relevant miR-29 target that has oncogenic potential in melanocytes and is required for growth of melanoma cells. Our findings suggest that MAPK-driven miR-29 induction constitutes a tumor suppressive barrier by targeting MAFG, which is overcome by attenuation of miR-29b2~c expression.
2023-04-10 | GSE148552 | GEO
Project description:Nearly 30% of all malignant melanomas harbor somatic mutations in NRAS. However, there are currently no effective targeted therapies for this tumor type. The bromodomain and extra terminal domain (BET) family of proteins are transcriptional regulators that serve as scaffolds to facilitate gene transcription by binding to acetylated lysine residues in the N-terminal tail of histones. BET/BRD proteins have emerged as therapeutic targets in a broad range of tumors. We found that BET proteins are overexpressed in NRAS mutant melanoma, and that high levels of BET family member BRD4 are associated with poor patient survival, suggesting that BRD4 plays a key role in melanoma. Consequently, we hypothesized that these epigenetic regulators constitute potential vulnerabilities that can be exploited for melanoma treatment. We found that genetic or pharmacological inhibition of BET/BRD proteins decreases viability and inhibits proliferation of NRAS mutant melanoma cells, as well as BRAF/MEK-inhibitor resistant melanoma cells harboring concurrent BRAF/NRAS mutations. However, BET inhibitors when used as single agents were either cytostatic (in vitro) or ineffective (in vivo). We therefore evaluated combinations that could maximize the efficacy of BET inhibitors in NRAS mutant melanoma. Here we report that co-targeting BET and MEK synergistically restrained tumor growth and significantly prolonged the survival of NRAS-mutant tumor bearing mice. RNA-sequencing and RPPA analysis revealed that co-treatment with BETi/MEKi synergistically downregulated cell cycle regulators and activated caspase-7. This study demonstrates that combined BET and MEK inhibition elicits robust synergistic therapeutic effects and supports the clinical utility of this combination therapy for NRAS mutant melanoma patients.
2018-02-20 | GSE95153 | GEO