Prahl, Louis2020-10-262020-10-262018-08https://hdl.handle.net/11299/216844University of Minnesota Ph.D. dissertation. August 2018. Major: Biomedical Engineering. Advisor: David Odde. 1 computer file (PDF); xii, 168 pages.Cell migration underlies the extensive tissue invasion that drives brain tumor (glioma) progression. Glioma cell migration involves the coordinated mechanical functions of the actin cytoskeleton, myosin motors, and substrate adhesions through a biophysical motor-clutch model. Although computational forms of the motor-clutch model predict glioma cell migration behaviors as a function of tissue stiffness, less is known about how other cellular structures such as microtubules influence migration. Presently, a number of microtubule-targeting agents (MTAs) are used to treat various cancers (including gliomas) so understanding their mechanism of action is necessary in order to develop better therapies. In this dissertation, I show that two commonly used MTAs (paclitaxel and vinblastine) each have distinct and nearly opposite effects on traction forces that motor-clutch simulations predict, and which correlate with changes to microtubule organization and dynamics. Effects of MTAs are consistent with influencing F-actin assembly and nucleation rates of protrusions, which impairs the ability of glioma cells to spontaneously polarize and migrate. Microtubule-dependent signaling networks that are perturbed in MTA-treated cells support novel roles for receptor tyrosine kinase (RTK) signaling pathways in mediating these effects. In the final study, we use microfabricated channels that replicate geometric and mechanical features of brain tissue alongside simulation-based methods to study confined glioma cell migration. Simulations recapitulate the dynamics of glioma cell migration in microchannels, as well as accurate predictions of the effects of MTAs and other pharmacological inhibitors of motor-clutch system components. This provides novel evidence for motor-clutch-based cell migration in confinement. In summary, this dissertation identifies specific mechanisms by which microtubules regulate motor-clutch based migration of glioma cells, and outlines a systems-level physics-based approach for understanding anti-motility therapy.enactincell migrationcomputational modelingcytoskeletongliomamicrotubuleThesis or Dissertation