title: Elucidating the mechanobiology of malignant brain tumors using a brain matrix-mimetic hyaluronic acid hydrogel platform.
abstract: Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by diffuse infiltration of single cells into the brain parenchyma, which is a process that relies in part on aberrant biochemical and biophysical interactions between tumor cells and the brain extracellular matrix (ECM). A major obstacle to understanding ECM regulation of GBM invasion is the absence of model matrix systems that recapitulate the distinct composition and physical structure of brain ECM while allowing independent control of adhesive ligand density, mechanics, and microstructure. To address this need, we synthesized brain-mimetic ECMs based on hyaluronic acid (HA) with a range of stiffnesses that encompasses normal and tumorigenic brain tissue and functionalized these materials with short Arg-Gly-Asp (RGD) peptides to facilitate cell adhesion. Scanning electron micrographs of the hydrogels revealed a dense, sheet-like microstructure with apparent nanoscale porosity similar to brain extracellular space. On flat hydrogel substrates, glioma cell spreading area and actin stress fiber assembly increased strongly with increasing density of RGD peptide. Increasing HA stiffness under constant RGD density produced similar trends and increased the speed of random motility. In a three-dimensional (3D) spheroid paradigm, glioma cells invaded HA hydrogels with morphological patterns distinct from those observed on flat surfaces or in 3D collagen-based ECMs but highly reminiscent of those seen in brain slices. This material system represents a brain-mimetic model ECM with tunable ligand density and stiffness amenable to investigations of the mechanobiological regulation of brain tumor progression.
authors.affiliation: Department of Bioengineering and California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA.
authors.forename: Badriprasad
authors.initials: B
authors.lastname: Ananthanarayanan
authors.forename: Yushan
authors.initials: Y
authors.lastname: Kim
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
mesh_terms: D001696:Biomechanical Phenomena / Q000187:drug effects; D040761:Biomimetic Materials / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005910:Glioma / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000737:chemistry; D020100:Hydrogels / Q000494:pharmacology*; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D020100:Hydrogels; D008689:Methacrylates; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D006820:Hyaluronic Acid