Effect of Omomyc on the in vivo growth of melanomas [SkMel147]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227842 | GEO | 2023/04/09
REPOSITORIES: GEO
Similar Datasets
Project description:Skin melanomas are highly aggressive and metastatic. Omomyc is the best MYC inhibitor currently available. We analysed the effect of Omomyc expression in a transgenic and inducible (upon Doxycycline addition) manner in melanoma cells in vivo in two different melanoma cell lines: A375 (mutated in BRAF), SkMel147 (mutated in NRAS). We used microarrays to detail the change in the gene expression programs induced by Omomyc on day 7.
2023-04-09 | GSE227841 | GEO
Project description:Skin melanomas are highly aggressive and metastatic. Omomyc is the best MYC inhibitor currently available. We analysed the effect of Omomyc expression in a transgenic and inducible (upon Doxycycline addition) manner in spontaneous lymph node metastases from SkMel147 (mutated in NRAS) melanoma cells in vivo. We used microarrays to detail the change in the gene expression programs induced by Omomyc on day 2.
2023-04-09 | GSE227843 | GEO
Project description:Skin melanomas are highly aggressive and metastatic. Omomyc is the best MYC inhibitor currently available. We analysed the effect of Omomyc expression in a transgenic and inducible (upon Doxycycline addition) manner in melanoma cells in vitro in A375 (mutated in BRAF) melanoma cell line. We used microarrays to detail the change in the gene expression programs induced by Omomyc on day 4.
2023-04-09 | GSE227840 | GEO
Project description:NRAS-mutated melanoma lacks an approved first-line treatment. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknow how the NRAS oncogene contributes to this cancer hallmark. Here, we show that NRASQ61-mutated melanomas harbor specific metabolic alterations that render cells sensitive to sorafenib upon metabolic stress. Mechanistically, these cells seem to depend on glucose metabolism, as glucose deprivation promotes the switch of the RAF isoform used from CRAF to BRAF. This process contributes to cell survival and sustains glucose metabolism through the phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/6- phosphofructo-2-kinase/fructose-2,6-bisphosph 3 (PFKFB2/PFKFB3) heterodimers by BRAF. In turn, this phosphorylation favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop linking glycolysis and the RAS signaling pathway. In vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with the combination of 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence of the contributions of NRAS oncogenes to metabolic rewiring and proof of principle for the treatment of NRAS-mutated melanoma with combinations of metabolic stress (glycolysis inhibitors) and already approved drugs such as sorafenib.
2023-01-09 | PXD028297 | Pride
Project description:Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-Seq analysis of laser-microdissected melanocytic nevi (n=23) and primary melanoma samples (n=57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbour signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbour signatures of anti-PD-1 antibody treatment resistance. Transcriptomic signatures suggest that the epigenetic regulators SMARCA2 and SMARCA4 are differentially involved in the epigenetic programming of the two melanoma types. Pseudotime dynamics of nevus and melanoma samples reflect a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy.
2018-07-19 | GSE112509 | GEO
Project description:NRAS and BRAF are the most commonly found genetic alterations in melanoma. It has been demonstrated that NRAS and BRAF oncogenic alterations, even affecting the same signaling pathway, represent two different clinical and biochemical entities, showing different signaling patterns and biological responses. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknown how the NRAS oncogene contributes to this cancer hallmark. We have showed that NRAS-mutated melanomas harbor specific metabolic alterations that render cells sensitive to RAS pathway inhibition upon metabolic stress. Gene expression analysis has confirmed different transcriptional profiles of NRAS- and BRAF- mutant cells both, under basal conditions and in response to glucose starvation. Moreover, analysis of glucose metabolism-related genes expression regulation revealed PFKFB2 as an important player linking glycolysis and RAS pathway activation.
2022-08-31 | E-MTAB-10921 | biostudies-arrayexpress
Project description:BRAF-inhibitor (BRAFi)-resistance compromises long term survivorship of malignant melanoma patients, and mutant NRAS is a major mediator of BRAFi-resistance. We have employed NanoString nCounterTM transcriptomic analysis of isogenic human malignant melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 versus BRAFi-resistant A375-BRAFV600E/NRASQ61K), identifying modulation of specific gene expression networks as a function of NRASQ61K-status.
2021-09-23 | GSE184633 | GEO
Project description:Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogenactivated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% ofmucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden. Keywords: melanoma, oncogene, comparative genomic hybridization, KIT
2006-09-09 | GSE4747 | GEO
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress
Project description:Malignant melanoma is characterized by frequent metastasis, however specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating beta-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and BrafV600E mutation, we demonstrate that beta-catenin is a central mediator of melanoma metastasis to lymph node and lung. In addition to altering metastasis, beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with beta-catenin stabilization are very similar to a subset of human melanomas; together these findings establish Wnt signaling as a metastasis regulator in melanoma. MoGene-1_0-st-v1: Four samples total. Two biological replicates of uncultured Pten/Braf murine melanomas and two biological replicates of uncultured Pten/Braf/Bcat-STA murine melanomas. MoEx-1_0-st-v1: Two samples total. Dissociated tumor and FACS-enriched Pten/Braf and Pten/Braf/Bcat-STA murine melanoma.
2011-10-12 | E-GEOD-32907 | biostudies-arrayexpress