Differential Molecular Function of RTKs in GBM Biology is Modulated by Sexual Dimorphism

Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor in adults and is diagnosed more often in males and in females. The current standard of care includes surgical resection, chemotherapy, and radiation therapy, though the tumor often recurs and overall survival for this disease remains low, necessitating the investigation of potential new nodes of treatment. In the search for individualized therapies for GBM, receptor tyrosine kinases (RTKs) have been discovered to mediate different responses and outcomes between male and female patients. This thesis aims to investigate the differential role two RTKs, EGFR and PDGFR, in mediating proliferation, migration, and invasion of GBM cells between males and females. Cell proliferation, migration, and invasion assays were performed using isogenic matched male and female murine GBM cell lines with specific RTK expression mimicking in vivo alterations to their respective oncogenes. Statistical analysis to compare the means of these markers was used to determine discrete trends in male and female cell lines, as well as between males and females with the same mutations. In vitro proliferation, migration, and invasion assays revealed distinct patterns of sex mediated molecular RTK function between males and females. EGFR and PDGFR expression were shown to play different roles in progression between these three metrics. Additionally, the used of an isogenic murine model with sex as a controlled variable allowed male-to-female comparisons, yielding data suggesting some RTKs may attenuate progression in one or more of these benchmarks in one sex more than the other. This study highlights the need for further investigation into the role RTKs play in male versus female GBM progression, which could potentially lead to the creation of new targeted treatments and personalized medicine approaches.