Rho GTPases in Glioblastoma Mechanobiology

Brain tumors are a source of morbidity and mortality worldwide, especially in children and young adults. Due to the high rates of inherently disabling effects (such as personality changes, visual disturbances, and poor coordination), many patients with brain tumors cannot live independently. Gliomas are one of the most common CNS tumors. Over 70% of gliomas are malignant, of which glioblastoma (GBM, WHO grade IV) is the most common and fatal brain tumor. The high-grade brain tumor cells (e.g., GBM cells) diffuse into the surrounding healthy tissue and promote a rapid tumor progression. Despite decades of extensive clinical and biological research, the mean survival time of patients with GBM is no more than 15 months following diagnosis. New perspectives and new approaches are needed for a better understanding on GBM progression and ultimately limit GBM invasion and recurrence. Eukaryotic cell migration is a multi-step process. Cells usually undergo cycles of extending membrane protrusion in the cell front, forming adhesion to interact with the surrounding microenvironment and contracting by actomyosin at the cell rear. Rho GTPases have been reported to play crucial roles in all these steps. Rho GTPases can alter their expression in cancer or cooperate with growth factor receptors to control cell invasion and metastasis. Abnormal expression, organization, and post-translational modification of ECM molecules are observed in solid tumor ECM, further stiffening the tissue ECM. The mechanics and organization of ECM can also regulate or modulate cell migration. During my PhD study, I have demonstrated that Rho GTPases and mechanical cues play critical roles in the GBM cell invasion. The main results of my thesis are as follows: 1. Rac1 depleting or inhibition dramatically reduces GBM cell invasion and changes their morphology with an abnormal cell cytoskeleton organization, myosin IIa location, and cell adhesion formation. 2. The Erk1/2 signaling is involved in Rac1 induced GBM cell invasion. 3. Inhibition of Rac1 changes GBM cell rigidity and viscosity.