Abstract
Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.
Overview
- The study investigates the influence of hyaluronic acid (HA) viscoelastic properties on glioblastoma (GBM) tumor invasion using hydrogels comprised of either high-molecular-weight (HMW) or low-molecular-weight (LMW) HA. The study aims to compare the invasion dynamics and leader-follower dynamics of GBM cells implanted in HMW and LMW HA hydrogels and to identify the mechanisms underlying these differences. The study uses transcriptomic, pharmacologic, and imaging studies to investigate the role of hyaluronidase in GBM invasion and argues for the use of highly stress-relaxing materials to model GBM.
Comparative Analysis & Findings
- The study found that GBM cells implanted in HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. The study argues that the stress-relaxing properties of HMW HA hydrogels are crucial for modeling GBM invasion and that these properties should be considered in future studies of GBM.
Implications and Future Directions
- The study highlights the importance of HA viscoelastic properties in GBM invasion and suggests that highly stress-relaxing materials should be used to model GBM. The study identifies hyaluronidase as a key player in GBM invasion and suggests that targeting this enzyme could be a promising therapeutic strategy. Future studies should further investigate the role of HA viscoelastic properties in GBM invasion and explore the use of other stress-relaxing materials for GBM modeling. The study also emphasizes the need for more translational research to bridge the gap between in vitro and in vivo models of GBM.