Mutational profile, stem cell and epithelial-mesenchymal transition markers in salivary gland mucoepidermoid carcinomas by cell type: targeted therapy application

• Grant number: 23/04287-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2024
• End date: August 31, 2027
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Fabio Daumas Nunes
• Grantee: José Martins Figueredo Junior
• Host Institution: Faculdade de Odontologia (FO). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Mucoepidermoid carcinoma (CME) is the most prevalent salivary gland malignant neoplasm, representing about 30% of all cases. Chemotherapy and radiotherapy are the standard treatments in advanced cases, but frequently they are unsuccessful. Epithelial-mesenchymal transition (EMT) is a transitory dynamic biological process with biochemical modifications which allow intermediate stages between epithelial and mesenchymal phenotypes. EMT has an important role in disease progression and treatment resistance and seems to enhance tumor cells with stem cell properties. Cancer stem-like cells (CSCs) are capable of self-renewal and multipotency, also contributing to metastasis development and treatment resistance. The aim of the present study is to analyze in detail the markers involved in these two processes and if they are related to CME's most frequent mutations and prognostic variables. A targeted therapy using inhibitors for one of these markers (Bmi1) is also going to be tested. Paraffin-embedded tumors will be micro-dissected by laser, selecting different cell types and analyzing the presence of different mutations (CRTC1/3-MAML2, CDKN2A, TP53, HMGA2 and BAP1) by PCR and DNA sequencing. EMT and CSCs markers will be analyzed by immunohistochemistry and RT-PCR, verifying if they have statistical associations with clinical and epidemiological parameters. Bmi-1 inhibitors will be tested combined or not with chemotherapy agents in translational studies in vitro and xenograft models in vivo.