Appreciation that the cell is involved in an intimate conversation with its microenvironment, and that biophysical inputs provide much of the backdrop to this conversation, underpins the field’s understanding of how cancer cells are able to invade healthy tissues. In particular, these processes are critical to the spread of the most malignant of all brain cancers, glioblastoma multiforme (GBM), in which aggressively infiltrating glioma cells spread remarkably quickly through the brain. GBM involves not only a slew of genetic lesions in participant cells, but also a range of biochemical and biophysical changes to the extracellular matrix (ECM) in which those cells reside. Recently, much evidence has emerged that one of those ECM components, hyaluronic acid (HA), and the cell membrane receptor to which it binds, CD44, plays a key role in pro -cancer biochemical signaling.
In this dissertation, we uncover another important characteristic of this ligand-receptor pair: that the material properties of HA can influence the signals transduced through CD44. We began with the development of an HA-based hydrogel to systematically study this ligand-receptor interaction using controlled HA density, controlled matrix stiffness, and controlled integrin conjugation. Using this platform, we then identified that HA matrix stiffness alone can instruct CD44-based cell adhesion and migration. Then, we began to investigate the underlying mechanisms which may be involved in CD44-based mechanosensing, by using genetic and pharmacological approaches to selectively inhibit potential downstream mediators in the ezrin-radixin-moesin (ERM) family proteins. While these targets did not result in changes, it narrows down the list of other potential candidates. Finally, we began to investigate how CD44 drives resistance to chemotherapy, and how this chemoresistance in turn can further enhance glioma invasiveness.
These discoveries enhance our understanding of how matrix properties enable cancer cell invasion, and could potentially lead to uncovering new strategies for intercepting the spread of glioma. Additionally, while the field has focused almost entirely on integrin- and cadherin- based mechanisms of mechanosensing, the studies described here support the idea that more consideration should be given to other ECM components.