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

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.