Study of SET and sphingolipids in head and neck cancer: signaling, targets and antitumor therapy

• Grant number: 18/17480-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2018
• End date: February 28, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Andréia Machado Leopoldino
• Grantee: Gabriel da Silva
• 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

Abstract

Despite the breakthrough in treating some cancers, the search for new therapeutic targets and antitumor therapy to prevent metastasis, relapse and resistance to therapy is needed. The present thematic proposal aims to define the role of the SET protein in the signaling pathway of sphingolipids, as well as their role in head and neck squamous cell carcinoma (HNSCC). Numerous experimental approaches will be used both in vitro and in vivo. We will conduct studies on human cell lines (derived from tumor and non-tumor), tumor samples, and serum from cancer patients. Different methods will be used to achieve the proposed objective, such as: (i) to perform in vitro screening of compounds with action on the metabolism of sphingolipids in HNSCC cell lines and then to confirm the antitumor potential of the selected compounds using nude mouse xenograft model; (ii) evaluation of sphingolipids in tumor and adjacent tissue samples from patients with HNSCC to identify potential associations with clinical-pathological characteristics, cell types of the tumor microenvironment (for example, myofibroblast) and angiogenesis; (iii) to determine the SET regulation mechanisms of transcription factors previously identified as SET targets, and to select common targets between SET and sphingosine-1-phosphate (S1P) signaling; (iv) carry out the ChIP-seq of samples with overexpression or silencing of sphingosine kinase (1 or 2) and SET to identify genes regulated by these proteins in HNSCC, and to confirm some of these genes as targets of these signaling pathways and S1P. These studies may both increase knowledge about sphingolipid signaling in head and neck cancer and lead to new mechanisms / therapeutic approaches for the treatment of cancer.

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)

FAEDO, RAQUEL ROMAN; DA SILVA, GABRIEL; DA SILVA, RODRIGO MOREIRA; USHIDA, TATIANE RESENDE; DA SILVA, RICARDO ROBERTO; LACCHINI, RICCARDO; MATOS, LEANDRO LUONGO; KOWALSKI, LUIZ PAULO; LOPES, NOBERTO PEPORINE; LEOPOLDINO, ANDREIA MACHADO. Sphingolipids signature in plasma and tissue as diagnostic and prognostic tools in oral squamous cell carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1867, n. 1, JAN 2022. (17/18922-2, 18/17480-9, 16/19103-2, 19/05026-4, 18/03278-3)

GOTO, RENATA NISHIDA; SOBRAL, LAYS MARTIN; STRINGHETTA-PADOVANI, KARINA; GARCIA, CRISTIANA B.; DA SILVA, GABRIEL; VITEK, MICHAEL P.; LEOPOLDINO, ANDREIA MACHADO. Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma. European Journal of Pharmacology, v. 882, SEP 5 2020. (13/00374-8, 13/01355-7, 13/10898-4, 18/17480-9, 16/19103-2, 13/08135-2)

DA SILVA, GABRIEL; BROCHERS-LACCHINI, FERNANDA COELI; LEOPOLDINO, ANDREIA MACHADO. How do sphingolipids play a role in epigenetic mechanisms and gene expression?. Epigenomics, v. 14, n. 5, p. 4-pg., 2021-12-15. (18/17480-9, 16/19103-2)