Exploring the Complexity of Ceramides in Head and Neck Cancer and Their Implications in the Processes of Angiogenesis and Oral Tumorigenesis

• Grant number: 23/17590-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2025
• End date: December 31, 2027
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Andréia Machado Leopoldino
• Grantee: Felipe Garcia Nishimura
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cancer, as one of the leading causes of global mortality, demands highly effective therapeutic approaches and the identification of highly specific biomarkers for accurate diagnosis and prognosis. In this context, sphingolipids emerge as key players due to their implications in the cancer landscape. Ceramide, a well-known sphingolipid with anti-tumoral properties, takes a prominent role. However, despite recognition, ceramides with variations in fatty acid chain structures remain largely unexplored. Furthermore, results obtained in the thematic project linked to this proposal have shown that certain ceramides are associated with prognostic parameters in oral cancer. In this current project, the objective is to deepen the understanding of the role played by these ceramides in the context of angiogenesis, therapy resistance, and the development of oral cancer. Through the CRISPR-CAS9 gene knockout technique targeting CerS1-6 genes, the intention is to elucidate the functional impact of ceramides, especially C16 and C18 species, in tumorigenesis and angiogenesis processes. Gene expression analyses through RT-qPCR and protein evaluations through Western Blot will examine changes in genes associated with angiogenesis at different ceramide concentrations. The understanding of cellular responses will be deepened through various in vitro and in vivo approaches, such as cell viability assays, proliferation assays, transmigration in transwell systems, tube formation, and in vivo assays using the chicken chorioallantoic membrane model for tumor formation through a xenograft model. In addition to these approaches, an international research collaboration has been established with Dr. Julie Gavard in France to study the interaction of these sphingolipids, SET protein, and cellular communication (such as extracellular vesicles) with implications in the regulation of angiogenesis and tumorigenesis. The project aims to fill gaps in current knowledge, aiming for future therapeutic advancements. In summary, this study seeks to explore less-studied ceramides in the proposed context, contributing to significant advancements in the cancer treatment landscape, while offering an innovative perspective in the realm of oncological research associated with sphingolipids.