Melanoma is a type of cancer that exhibits significant heterogeneity and can vary considerably from one patient to another.

As a result, precision medicine has emerged as a promising approach to its treatment.

Identifying and analyzing new predictive and/or prognostic biomarkers has helped narrow the gap between basic research and the actual treatment of patients by facilitating the prediction of treatment responses and potential adverse events. RNA-seq analysis provides valuable insights into the gene signatures and mechanisms that drive melanoma development in its early and late stages, with important implications for diagnostics and therapy.

The ‘Dataset Roundup' series features datasets on Polly that are of scientific value, intended to promote data sharing and reuse of biomedical molecular data. In this roundup, we provide a snapshot of some of the interesting Bulk RNA seq datasets on melanoma. The bulk RNA seq data on Polly is annotated, harmonized, and consistently processed through Kallisto pipelines. This data is ready for consumption in downstream analysis and is stored in an ML-ready format so that it can be input. You can find more highly curated Bulk RNA seq datasets on melanoma (see figure below) and many other diseases from different repositories that can be visualized and analyzed using our DataOps platform, Polly.

Dataset 1

Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment.

Dataset ID: GSE153556_GPL13112
Year of Publication: 2020
Total samples: 24
Data type: BulkRNASeq
Organism: Mus musculus
Reference link: Publication, Raw data

Summary

Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, the authors identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation.

In the TME, monocyte-macrophage lineage cells produced glucocorticoids, and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.

‍Dataset 2

Gene expression changes detected in mouse melanomas after conditional genetic inactivation of ezh2 using tyr: Cre-ERT2 on a braf;pten genetic background

Dataset ID: GSE192491_GPL17021
Year of Publication: 2021
Total samples: 7
Data type: BulkRNASeq
Organism: Mus musculus
Reference link: Publication, Raw data

Summary

Histone 3 methyltransferases alter melanoma initiation and progression through discrete mechanisms. Perturbations to the epigenome are known drivers of tumorigenesis. In melanoma, alterations in histone methyltransferases that catalyze methylation at histone 3 lysine 9 and histone 3 lysine 27-two sites of critical post-translational modification- have been reported. To study the function of these methyltransferases in melanoma, melanocytes were engineered to express histone 3 lysine-to-methionine mutations at lysine 9 and lysine 27, which are known to inhibit the activity of histone methyltransferases in a zebrafish melanoma model.

Using this system, the authors found that loss of histone 3 lysine 9 methylation dramatically suppressed melanoma formation and that inhibition of histone 3 lysine 9 methyltransferases in human melanoma cells increased innate immune response signatures. In contrast, histone 3 lysine 27 methylation loss significantly accelerated melanoma formation. They identified FOXD1 as a top target of PRC2 silenced in melanocytes and found that aberrant overexpression of FOXD1 accelerated melanoma onset. Collectively, these data demonstrate how histone 3 lysine-to-methionine mutations can be used to uncover critical roles for methyltransferases.

‍Dataset 3

Characterization of tumor-associated macrophages (TAM) in the tumor microenvironment of human melanoma

Dataset ID: GSE171277_GPL28038
Year of Publication: 2021
Total samples: 39
Data type: Bulk RNASeq
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary

CCL20/TNF/VEGFA cytokine secretory phenotype of tumor-associated macrophages is a negative prognostic factor in cutaneous melanoma. TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. This article explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; also, because cytokine production is a hallmark of macrophages function, and measured CCL20, TNF and VEGFA intracellular cytokines by single-cell multiparametric confocal microscopy. The Kaplan-Meier method was used to analyze the correlation between melanoma-specific disease-free survival and overall survival. No significant correlations with clinical parameters were observed for TAM density, morphology, or location.

Significantly, higher contents of the intracellular cytokines CCL20, TNF, and VEGFA were quantified in TAMs infiltrating metastasizing compared to non-metastasizing skin primary melanomas (p < 0.001). To mechanistically explore cytokine up-regulation, the authors performed in vitro studies with melanoma-conditioned macrophages, using RNA-seq to explore involved pathways and specific inhibitors. They showed that p53 and NF-κB coregulate CCL20, TNF, and VEGFA in melanoma-conditioned macrophages. These results delineate a clinically relevant pro-oncogenic cytokine profile of TAMs with prognostic significance in primary melanomas and point to the combined therapeutic targeting of NF-kB/p53 pathways to control the deviation of TAMs in melanoma.

Dataset 4

Treatment of melanoma cell lines with CCG-222740

Dataset ID: GSE134320_GPL20301
Year of Publication: 2019
Total samples: 40
Data type: Bulk RNASeq
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary

Inhibition of the myocardin-related transcription factor pathway increases the efficacy of Trametinib in NRAS-mutant melanoma cell lines. The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, the authors demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines.

A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

Dataset 5

Patient-derived xenograft platform for metastatic melanoma: a model for studying resistance to targeted therapy.

Dataset ID: GSE66539_GPL11154
Year of Publication Update: 2019
Total samples: 14
Data type: BulkRNASeq
Organism: Homo sapiens
Reference link: Publication 1, Publication 2, Raw data

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts. The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. In vivo systems are needed to allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, the authors established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms.

They identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

Because of its structured and harmonized repositories, Polly allows complex queries and generates accurate search results on bulk and single-cell RNA-seq data. Take a look at various Python notebooks for examples of the consumption of your data here.

Connect with us to accelerate your journey of finding relevant biomedical datasets, creating cohorts, visualizing and analyzing the data, thereby deriving actionable insights and probable targets.