RMEL3, a positive regulator of MHC Class II and Lysophosphatidic Acid (LPA) pathways, as a novel mediator of immunosuppression in melanoma

• Grant number: 25/21581-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2025
• End date: August 31, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Enilza Maria Espreafico
• Grantee: Daniel Henrique Rattis Lemos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/17621-0 - Translating non-coding RNA signatures into novel biomarkers and therapeutic targets in Melanoma, AP.TEM

Abstract

Melanoma is one of the most aggressive skin tumors, characterized by high mortality rates at metastatic stages and pronounced molecular heterogeneity. Despite recent advances in immunotherapy, only a fraction of patients achieve lasting responses, underscoring the need for new biomarkers and therapeutic targets. In this context, long non-coding RNAs (lncRNAs) have emerged as important regulators of tumor biology, acting in multiple cellular and immunological processes. Among them, RMEL3 shows restricted expression in melanomas and a strong association with the BRAFV600E mutation, suggesting a determinant role in disease progression. Evidence indicates that RMEL3 silencing compromises pathways associated with cell survival, extracellular matrix remodeling and adhesion, in addition to affecting the expression of genes involved in antigen presentation via MHC class I and II and immune checkpoint regulators. Another finding is that RMEL3 positively regulates the lysophosphatidic acid (LPA) pathway, a bioactive lipid that promotes pro-invasive phenotypes, cytoskeletal remodeling, and immune evasion through inhibition of TCR signaling in CD8+ T lymphocytes, positioning it as a potential mediator of immunosuppression in melanoma. It is assumed that RMEL3 acts as a pleiotropic regulator capable of promoting an inflammatory and immunosuppressive tumor microenvironment, favoring migration, invasion, and survival of melanoma cells while contributing to immune escape. The project aims to investigate the functional and regulatory roles of this lncRNA and its relevance in disease progression, identifying mechanisms that may be explored as therapeutic vulnerabilities. Comprehensive molecular and functional approaches will be employed, both in vitro and in vivo. One of the main focuses will be to expand global genomic and transcriptomic studies in order to clarify RMEL3's contribution to the regulation of immunomodulatory genes in melanoma and to mechanisms of chemoresistance to BRAF and MEK inhibitors. In addition, a murine experimental model of melanoma progression will be explored to assess RMEL3's transforming potential and its ability to modulate invasive and metastatic phenotypes at different stages of the disease. For this purpose, RMEL3 expression will be conditionally induced in immortalized melan-a melanocytes and in cell lines representative of tumor progression, including 4C (premalignant), 4C11- (non-metastatic melanoma), and 4C11+ (metastatic melanoma). This model will enable the evaluation of RMEL3's influence on tumor growth, microenvironment modulation, and metastasis in both immunocompetent and immunodeficient systems, as well as the testing of potential therapeutic interventions based on antisense oligonucleotides and immune checkpoint inhibitors. This project is expected to elucidate immune evasion mechanisms mediated by RMEL3, clarify its relationship with tumor remodeling pathways and chemoresistance, and identify new molecular vulnerabilities. The results hold potential to support the development of prognostic and therapeutic response biomarkers, as well as to open perspectives for innovative strategies in melanoma immunotherapy. Thus, the proposal combines scientific relevance with translational applicability, with an expected impact on advancing knowledge of melanoma biology and on the development of new approaches for its clinical management. (AU)