Translational control of mRNAs encoding primary cilia components in glioblastomas

• Grant number: 20/14045-0
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2022
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Glaucia Noeli Maroso Hajj
• Grantee: Glaucia Noeli Maroso Hajj
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Douglas Guedes de Castro ; Felipe D'Almeida Costa ; Glaucia Noeli Maroso Hajj ; Tommy Alain ; Tyson Graber ; Vilma Regina Martins ; Warley Abreu Nunes

Abstract

Glioblastoma (GBM) is the most malignant and deadly brain tumor. Even with standard treatment, virtually all GBMs recur in months. High-throughput studies of GBMs resulted in several molecular classifications based on mRNA levels (transcriptome), however, they have not been useful in the clinic. One possible factor is that the final functional product of most genes is a protein. Our laboratory analyzed the fraction of mRNAs that are being actively translated to form proteins (translatome) in cases of GBMs and identified changes in gene expression not detected in the transcriptome. We observed that mRNAs that encode proteins related to the primary cilium (PC), an organelle involved with oncogenic cell signaling, were reduced in the translatoma of patients with prolonged survival, but not in their transcriptome. One of these mRNAs encodes the PCM1 protein, necessary for the formation of PC and resistance to temozolomide, which is used in the standard treatment of GBM. The present proposal aims to identify the translation control mechanisms of these mRNAs (PC-mRNAs). Preliminary data suggest that PC-mRNA translation would occur through specific, and probably unprecedent, mechanisms in GBMs. We will integrate ribosome profiling, bioinformatics, biochemical and cell biology experiments to identify the determinants of the specific translation of PC-mRNAs. We will verify whether the modulation of these mRNAs and/or translation control mechanisms affects the dynamics of the PC and the resistance to treatment. We will reinforce the relevance of the proposal, by analyzing the presence of PCs and the expression of proteins encoded by PC-mRNAs in GBM cases, and their relationship with clinical data, mainly survival and resistance to treatment. (AU)