Mechanisms of adhesion and invasion in hyaluronic acid matrices

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PROJECT SUMMARY/ABSTRACT Hyaluronic acid (HA) is the most abundant component of the human brain, where it serves essential structural, mechanical, and cell-instructive functions. Adhesion between HA and its receptor CD44 critically regulates development and homeostasis, and dysregulation of HA and/or CD44 causally drives many brain pathologies, including invasion of the deadly brain tumor glioblastoma (GBM). Despite the clear biological significance of HA-CD44 adhesion, comparatively little is known about either the biophysical mechanisms through which HA- CD44 interactions drive cell adhesion, migration, or matrix remodeling or how HA composition (e.g. molecular weight) influences adhesion and migration. Over the past decade, our team has made seminal contributions to addressing these questions, including introducing and refining synthetic 3D HA matrices as a culture model for studying GBM invasion. We also discovered that CD44 transduces HA-based mechanical signals to regulate cell shape, cytoskeletal assembly, and motility. Most recently, we discovered that GBM cells engage HA using “microtentacles” (McTNs), CD44-dependenent processes that extend tens of microns from the cell body, are associated with HA digestion, and mechanically couple to the cytoskeleton through a complex that includes IQGAP1 and CLIP170. McTNs bear important similarities to structures that have been observed in invasive GBMs in vivo, and overexpression of McTN components is predictive of with aggressive progression and poor survival in GBM. In this R01 application, we will leverage these discoveries and biomaterial platforms to advance the field’s understanding of how HA and CD44 contribute to cell adhesion, migration, and invasion. In our first aim, we will investigate how McTNs facilitate adhesion, invasion, and matrix remodeling. In our second aim, we will determine how biophysical features of the HA network in brain tissue contributes to 3D migration, using GBM as a model system. Our approach is distinguished by tight integration of engineered biomaterial culture models, mouse models featuring human GBM stem/initiating cells, and analysis of biopsies obtained from specific anatomic regions of human GBMs. Our multi-institutional team also uniquely combines expertise in biomaterials, mechanobiology, neurosurgery, and cancer biology. Successful completion of these studies will yield unprecedented insight into the biophysical basis through which HA and CD44 contribute to adhesion and invasion, a problem of high fundamental interest that may lead to novel therapeutic targets in GBM.