Chemo and radioresistance of glioblastomas: the role of DUSP12 phosphatase and Rho GTPase

• Grant number: 24/13597-0
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2025
• End date: December 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Fábio Luis Forti
• Grantee: Fábio Luis Forti
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Erico Tosoni Costa ; Niels Olsen Saraiva Câmara

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor that grows and spreads quickly. Its malignancy is also due to high resistance to conventional therapies, poor prognosis and high post-therapy recurrence rate with survival of only 1-2 years. Previous work by the group contributed to new proposals for molecular targets that offer an advantage in pre-sensitizing tumor cells and reducing resistance to therapies. We show that the Rho GTPases pathway and actin cytoskeleton remodelers are important mediators not only for the motility, invasiveness and genomic stability processes of these cells, but also appear to be mediating the tumor stemness properties of resistant GBMs. On the other hand, the double phosphatase DUSP12, little explored in GBMs and with an important role in hepatocellular carcinoma (HCC), may be another molecular target acting on the response of these cells to conventional therapies. This project intends to focus on two distinct molecular fronts, but aiming for the same result: chemo- and therapeutic radioresistance of GBMs. To this end, we will use monolayer cell models and spheroids of normal chemoresistant and radioresistant GBMs developed in our laboratory and will subject them to modulation: 1st) of the Rho GTPases pathway and actin cytoskeleton and 2nd) of the DUSP12 phosphatase and one of its nuclear targets, the protein NAT10, which in HCC and other cancers has been shown to be an important regulator of the cell cycle, DNA repair, chromatin organization, gene expression and nuclear architecture, unique processes for maintaining genomic stability that are essential in transformation and /or tumor resistance. (AU)