Mechanobiological Regulation of Glioblastoma Initiation and Invasion
Glioblastoma remains elusive to treat due to the diffuse infiltration of single tumor cells into the surrounding tissue. Current standard therapies - surgery, radiation, chemotherapy - have been ineffective at significantly increasing survival time. Although many studies have focused on factors that affect glioma growth and invasion, it is still unclear how and why this disease is so aggressive. Promising chemotherapeutic drugs have failed in clinical trials even though specific targets were identified. The existence of tumor-initiating cells (TICs), a subpopulation within primary tumors, could explain how the heterogeneous makeup of the bulk tumor leads to quick adaptability to resist surrounding cues that limit migration and growth. The work presented in this dissertation has approached this problem from a biophysical perspective, demonstrating that the extracellular matrix (ECM) can serve as a regulator of TIC invasion and initiation both in vitro and in vivo.
We first characterized TIC migration and growth on 2D ECMs and found that they were able to migrate readily even on soft ECMs. Noting that cellular contractility is important for cells to sense environmental cues in the surrounding tissue, we manipulated the TICs with upregulation of myosin activators. Thus, we were able to rescue mechanosensing in the TICs and found that migration of the CA RhoA TICs was limited on soft ECMs. We then used 3D invasion assays to confirm that high contractility in TICs limits invasion and migration in 3D as well. Lastly, we implanted CA RhoA TICs in orthotopic mouse models and found that increased cellular contractility limits tumor occupancy and significantly increases survival time.