As the most common malignant primary brain tumor, GBM represents a significant disease burden. GBM tumor cells disperse extensively throughout the brain parenchyma, and the need for tumor-specific drug targets and pharmacological agents to inhibit cell migration and dispersal is great. Furthering our understanding of the molecular mechanisms responsible for GBM cell migration will undoubtedly aid in this endeavor. PTPμ is a homophilic CAM that regulates cell migration in the CNS. This dissertation demonstrates that full-length PTPμ is downregulated in human GBM. Furthermore, downregulation of PTPμ in human glioma cells induces migration in vitro in part due to Rac1-mediated lamellipodial formation and cell polarization. These changes in migratory phenotype and morphology were recapitulated in an ex vivo brain slice model and an in vivo xenograft model, respectively.
Additionally, proteolytic cleavage is shown to be the mechanism of PTPμ downregulation in GBM cells. Proteolysis of PTPμ generates a soluble catalytic intracellular domain fragment termed PTPμ ICD that translocates to the nucleus. Furthermore, proteolyzed PTPμ fragments are detected in human GBM. shRNA-mediated downregulation of PTPμ fragments decreases GBM cell migration and growth factor-independent survival. A peptide inhibitor of PTPμ function blocks PTPμ fragment-induced GBM cell migration, which may prove to be of therapeutic value in GBM treatment. These studies suggest that full-length, cell surface PTPμ is downregulated by proteolysis to generate a catalytically active PTPμ fragment that contributes to the migration and survival of GBM cells. Targeting this fragment pharmacologically could limit the dispersal of GBM cells and greatly enhance the management of GBM patients.