Investigating the role of CARM1-mediated methylation of Qki in glioblastoma

PROJECT SUMMARY Glioblastoma (GBM), the most common and deadly form of primary brain tumor in adults, is defined by high molecular heterogeneity that renders tumors highly refractory to therapy. Glioblastoma stem cells (GSCs) are a key population within this heterogeneity, harboring proliferative and self-renewal capacities to promote growth, invasion, and resistance. Deciphering key mechanisms of GSC maintenance during gliomagenesis will inform the development of novel GBM therapeutic strategies. Our lab has characterized Quaking (Qki), which is lost in 50-60% of GBM cases, as an important GBM tumor suppressor. Deletion of Qki in a pre-malignant genetic mouse model induces the formation of GBM tumors. Mechanistically, Qki functions as a transcriptional co-activator that regulates both the protein and lipid compartments of the endolysosomal system. Notably, Qki loss compromises endolysosomal degradation and enriches self-renewal receptors at the cell surface, enabling GSCs to maintain stemness and expand outside their niche. It remains to be explored whether other mechanisms of Qki dysregulation govern the maintenance of GSCs in cases where Qki remains intact. Cancer genomic data reveals recurrent mutations to specific Qki arginine residues that implicate the dysregulation of arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs). Previous studies reveal that Qki interacts with a PRMT called co-activator associated arginine methyltransferase 1 (CARM1), and our preliminary data shows that Qki is selectively methylated by CARM1. In this proposal, I intend to elucidate the role of CARM1- mediated methylation of Qki in the maintenance of GSCs during gliomagenesis. By establishing stable Qki methylation mutant cell lines and generating a novel genetic mouse model with the brain-specific deletion of CARM1 on a pre-malignant background, I will employ a range of molecular, cellular, bioinformatic, and lipidomic experimental approaches with aims to 1) characterize the molecular function of CARM1-mediated methylation of Qki and 2) determine the impact of Qki arginine methylation on endolysosomal degradation and gliomagenesis. Successful completion of this proposal will provide critical insight into novel pathomechanisms underlying GBM and illuminate new GBM therapeutic strategies that utilize Qki methylation status as a determinant for patient stratification. Moreover, this proposal will provide me, the Principal Investigator, with rigorous technical training and valuable experiences tailored for my development as an innovative researcher. The lab of my sponsor Dr. Jian Hu at MD Anderson Cancer Center represents an exceptional environment for me to complete my project. Additionally, my co-sponsor Dr. Mark Bedford provides critical mentoring, scientific expertise, and technical support to enrich my project and education. With my graduate program, I will receive extensive training in the foundations and applications of cancer biology and varied opportunities to prepare me for my career goal of becoming an independent academic researcher.