Characterization of Sig-1R in the immune and metabolic response of sphingolipids as a chemoresistant factor in oral cavity cancer

• Grant number: 21/03732-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: February 01, 2022
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Andréia Machado Leopoldino
• Grantee: Pablo Shimaoka Chagas
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 16/19103-2 - SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy, AP.TEM
• Associated scholarship(s): 22/07821-9 - Establishment of a Zebrafish model to study the role of SIGMAR1 in oral cancer-immunity cycle, BE.EP.PD

Abstract

Squamous cell carcinoma of the oral cavity (OSCC) is a malignant tumor and the main cause of morbidity and mortality among all cancers of the head and neck. It is an immunosuppressive disease, metastatic and highly resistant to conventional treatments. Recent studies have identified that biomolecules of the metabolic pathway of sphingolipids (SPs) are involved in the immunoregulation of the progression and resistance of this tumor. The Sigma-1 Receptor (Sig-1R) is characterized as a biomarker of the worst prognosis and promising therapeutic target in several cancers, and it seems that a cross-talk between the antitumor immunity pathway (PD-1 / PD-L1) and SP metabolism is indicated. In the quest to reactivate antitumor immunity, we intend to characterize Sig-1R in OSCC in vitro and in vivo by developing Knockdown models of Sig-1R by siRNA in OSCC strains. Subsequently, these cells will be treated with chemotherapy and functional tests will be carried out. Immunofluorescence analyzes, co-immunoprecipation; RNA-seq, protein array and mass spectrometry will be performed to mechanically dissect the complex molecular interactions between Sig-1R / PD-L1 and Sig-R1 / SPs. The Zebrafish embryo editing technique will be performed to evaluate the same treatment and the characterization of tumor infiltrating lymphocytes will be performed by flow cytometry. The expectation is that the conclusion of this project will clarify aspects of the regulation of OSCC resistance and that this information can be used to improve the prognosis and treatment of the disease.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CHAGAS, PABLO SHIMAOKA; GARCIA, CRISTIANA BERNADELLI; SOUSA, LUCAS OLIVEIRA; DA SILVA, GABRIEL; DE SOUSA, GRAZIELLA RIBEIRO; MARCELINO, RODOLFO CABRAL; DE MATOS, LEANDRO LUONGO; KOWALSKI, LUIZ PAULO; SALLES, EVILA; WANG, LEI; et al. SIGMAR1 Knockdown Enhances Oral Cancer Cell Chemosensitivity to Cisplatin via Decreased PD-L1 Expression. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 22, p. 13-pg., 2024-11-01. (21/03732-9, 22/07821-9, 16/19103-2)