Identification and characterization of ncRNAs playing a role in Melanoma phenotypic plasticity

• Grant number: 22/00322-7
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2022 - October 31, 2024
• 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

Abstract

Tumor cell plasticity contributes to metastatic competence and is related to tumor heterogeneity, reccurence and treatment failure. Melanomas have high propensity to metastasis and frequently become drug resistant. Although patient survival has significantly increased with the more recent therapeutic modalities, as molecular targeted therapies and immunotherapies, majority patients present reccurence and drug resistence. The extremely plastic and dynamic nature of Melanoma has been revealed by several studies, specially recently with the advances in single cell analyses. Two classic phenotypic states were inicially described: poor proliferative, undifferentiated and mesechymal-like cells, and differentiated, melanocytic and highly proliferative cells. Other intermediate cell states were described, mainly emerging after treatments. The major studies investigate the transcriptional profile and transcription factor involved in different phenotypic states. In the last years, we have explored molecular alterations in a linear cellular model of Melanoma progression, with the same genetic background, established in our laboratory. This model consists of parental non-tumorigenic melanocytes (melan-a), pre-malignant melanocytes (4C), non-metastatic Melanoma cells (4C11-) and metastatic Melanoma cells (4C11+). High throughput molecular analyses revealed that this model, besides a valuable model for the identification of early and late alterations taking place along Melanoma progression, is also suitable to the study of cell plasticity. Differentiated melan-a melanocytes change to a poor proliferative, undifferentiated and mesenchymal-like state in the trnsition to 4C pre-malignant melanocytes. 4C11- Melanoma cells, presenting a similar phenotype that 4C, change to a differentiated, melanocytic and highly proliferative phenotype in the transition to 4C11+. Evidences have clearly shown the role of non-genetic mechanisms in the regulation of phenotype switching. Alterations in noncoding RNA (ncRNA) expression, including miRNAs and lncRNAs, contribute to the tumor development and progression. However, studies about their role in the Melanoma phenotypic switching are still scarse, Thus, this project aims to identify and characterize the role of ncRNAs in Melanoma phenotypic reprogramming. (AU)