UC Berkeley

In the past two decades, glioma stem cells (GSCs) have been increasingly implicated in driving tumor initiation, resistance, recurrence, growth and invasion in glioblastoma (GBM). Despite in vivo evidence identifying GSCs at invasive regions of GBM tissue, GSC invasion and by extension motility has been less well appreciated. Furthermore, GBM tumor invasion is informed by a multitude of biochemical factors, such as cytokines and growth factors, and biophysical factors, such as matrix and stroma geometry and mechanics. GBM tumors invade slowly through the hyaluronic acid (HA)-rich parenchyma and then rapidly along microvascular tracks of varying geometries. How biophysical and biochemical factors together contribute to driving invasion of GBM tumor cells such as GSCs within these regions is not well understood. Progress in understanding this combinatorial effect is limited by a lack of physiologically representative cell culture models that can enable systematic investigations to gain better understanding of regulators of invasion.

In this dissertation, we first applied an HA-based hydrogel model of the brain parenchyma to study transforming growth factor beta (TGF- β) induced invasion of GSCs. We demonstrate that in response to TGF-β, GSCs differ in their ability to invade HA in a way that can be predicted from TGF-β receptor 2 expression and SMAD2 phosphorylation. Additionally, we found an association between TGF-β responsiveness and GSC subtype. Interestingly, TGF- β stimulated GSC invasion exhibited a strong dependence on the presence of RGD peptides. Next, we deployed protein micropattern lines with vessel-like geometries to understand the emergent cell migration behavior of GSCs along a confined environment. We tested multiple GSC lines and found that vessel-like geometries enhanced both migration speed and persistence in GSCs. However, no individual GSC line demonstrated both enhanced migration speed and persistence, suggesting that vessel-like geometric confinement differentially influence migration dynamics of GSCs.