Translating non-coding RNA signatures into novel biomarkers and therapeutic targets in melanoma

• Grant number: 23/17621-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2025
• End date: May 31, 2030
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Miriam Galvonas Jasiulionis
• Grantee: Miriam Galvonas Jasiulionis
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: Eduardo Moraes Rego Reis ; Enilza Maria Espreafico
• Associated researchers: Alexander Birbrair ; Frank John Slack ; Gangning Liang ; Hatylas Azevedo ; Jeremie Nsengimana ; Jeremy E Wilusz ; João Carlos Setubal ; João Pedreira Duprat Neto ; Leticia Fröhlich Archangelo ; Marcos Simoes Costa ; Renato Santos de Oliveira Filho ; Ricardo Guelerman Pinheiro Ramos ; Tathiane Maistro Malta Pereira ; Thiago Aparecido da Silva ; Vinicius de Lima Vazquez

Abstract

Melanoma is one of the most aggressive and therapy-resistant neoplasias. Despite advances achieved through the development of targeted therapies, such as BRAF and MEK inhibitors, and immunotherapies, such as anti-CTLA4 and anti-PD1, which have resulted in increased survival of patients with malignant melanoma, around 50% of these develop resistance to treatments. The characteristic phenotypic plasticity of melanoma, which recapitulates phenotypic changes that occur during the differentiation of melanocytes from neural crest stem cells, contributes significantly to tumor heterogeneity and is correlated with worse patient survival. The reactivation of embryonic development pathways contributes to adaptation to hostile environments, facilitating melanoma progression, metastatic dissemination and therapeutic resistance. Melanoma cells with distinct transcriptional programs have been described both in cell cultures and in melanoma samples, including in the same tumor. Tumor microenvironment conditions, as well as therapies, are capable of modifying the phenotypic state of melanoma cells, resulting in the emergence of different cell subpopulations, including treatment-tolerant cells and dormant cells. Analysis of primary and metastatic melanoma samples from the same patient were unable to identify metastasis-causing mutations ("drivers"), pointing to the role of epigenetic mechanisms in controlling the change in phenotypes. Important changes in chromatin structure associated with epigenetic alterations, such as DNA methylation, histone modifications, and regulation by non-coding RNAs, allow for rapid and reversible changes in gene expression and are observed in changing melanoma phenotypes. Among these mechanisms, long non-coding RNAs (lncRNAs) have shown a central role in epigenetic circuits that control complex biological processes, such as developmental programs. Its diverse mechanisms of action include targeting chromatin-modifying enzymes to specific promoters, forming platforms for recruiting ribonucleoprotein complexes, removing proteins from transcriptional sites, sequestering miRNAs, acting as miRNA precursors, blocking enhancers for the formation of chromatin loops and impediment of mRNA translation, making lncRNAs candidates for effective regulators of the dynamic change of transcriptional states, therefore being attractive therapeutic targets. Despite the increasing number of studies revealing transcriptional states that define subpopulations of melanoma cells of different phenotypes, knowledge about the molecular basis of this plasticity is still scarce. The identification of vulnerabilities of melanoma cells of different phenotypic states and, in particular, of regulators of phenotypic plasticity can facilitate the development of therapeutic strategies capable of preventing the emergence of resistant subpopulations. Since developmental states are associated with response to therapies, a possible strategy would be to target lncRNAs that control cellular states, sensitizing melanoma cells to therapies such as targeted therapies and immunotherapies. (AU)