The Transcriptional Landscape of BRAF Wild Type Metastatic Melanoma: A Pilot Study

Abstract

Melanoma is a relatively rare disease worldwide; nevertheless, it has a great relevance in some countries, such as in Europe. In order to shed some light upon the transcriptional profile of skin melanoma, we compared the gene expression of six independent tumours (all progressed towards metastatic disease and with wild type BRAF) to the expression profile of non-dysplastic melanocytes (considered as a healthy control) in a pilot study. Paraffin-embedded samples were manually micro-dissected to obtain enriched samples, and then, RNA was extracted and analysed through a microarray-based approach. An exhaustive bioinformatics analysis was performed to identify differentially expressed transcripts between the two groups, as well as enriched functional terms. Overall, 50 up- and 19 downregulated transcripts were found to be significantly changed in the tumour compared to the control tissue. Among the upregulated transcripts, the majority belonged to the immune response group and to the proteasome, while most of the downregulated genes were related to cytosolic ribosomes. A Gene Set Enrichment Analysis (GSEA), along with the RNA-Seq data retrieved from the TCGA/GTEx databases, confirmed the general trend of downregulation affecting cytoribosome proteins. In contrast, transcripts coding for mitoribosome proteins showed the opposite trend.

Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines

“…In contrast, the higher LY3009120 concentrations induced an elevated metabolic activity, indicating a potential to trigger an alternative pathway activation similar to a feedback mechanism or paradoxical hyperactivation effect. Similarly, for the LY3009120-resistant equine melanoma cell line (eRGO6), the cause of resistance may be due to its accompanying molecular alterations, like the loss of tumor suppressor genes such as the TP35, PTEN, CDKN2A, RB1, SPARC, and PI3K/AKT pathway mutations, alterations in cell translational machinery (cytosolic ribosomal proteins (rProteins)) [35], and the dysregulation of the metabolism (HMOX1) [36]. Further, the compensatory mechanisms and adaptive reconnecting between the PI3K/AKT/mTOR and RAF/RAS/MEK/ERK pathways may also influence resistance mechanisms [37].…”

Advances in Immunotherapy and Innovative Therapeutic Approaches for Cancer Treatment: Editorial to the Special Issue “State-of-the-Art Molecular Oncology in Italy”

“…The authors compared the gene expression of six independent tumors (all progressed towards metastatic disease) to the expression profile of non-dysplastic melanocytes (considered a healthy control) using gene set enrichment analysis (GSEA) and RNA-Seq data retrieved from the TCGA/GTEx databases. The results showed a distinct upregulation of the genes involved in the immune response (i.e., major histocompatibility complex (MHC) class I and class II pathways) and proteasome activity, as well as transcripts related to mitoribosome proteins, whereas those related to cytosolic ribosome proteins showed decreased expression compared to that of healthy controls [25]. Although this pilot study analyzed a small group of patients, the immune profiles obtained by the authors may potentially help in predicting the responsiveness of BRAF wild-type metastatic melanoma to immunotherapy and highlight the importance of protein synthesis and degradation for cancer cell survival in this pathology, thus allowing the identification of the best therapeutic approach for these patients [25].…”

“…As discussed previously, the discovery of new molecular targets for tumor treatment also relies on a detailed characterization of the genomic and transcriptional profiles of each cancer patient to develop a "personalized" therapy. In their pilot study, Lastraioli et al focused their attention on BRAF wild-type metastatic melanoma, which currently lacks an efficient targeted therapy [25]. The authors compared the gene expression of six independent tumors (all progressed towards metastatic disease) to the expression profile of non-dysplastic melanocytes (considered a healthy control) using gene set enrichment analysis (GSEA) and RNA-Seq data retrieved from the TCGA/GTEx databases.…”