Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM,...

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Bibliographic Details
Published in:Advanced healthcare materials 2023-06, Vol.12 (14), p.e2203143-n/a
Main Authors: Safarians, Gevick, Sohrabi, Alireza, Solomon, Itay, Xiao, Weikun, Bastola, Soniya, Rajput, Bushra W., Epperson, Mary, Rosenzweig, Isabella, Tamura, Kelly, Singer, Breahna, Huang, Joyce, Harrison, Mollie J., Sanazzaro, Talia, Condro, Michael C., Kornblum, Harley I., Seidlits, Stephanie K.
Format: Article
Language:English
Subjects:
Actin
Brain
Brain - pathology
Brain cancer
CD44
CD44 antigen
Cell adhesion & migration
Cell Line, Tumor
Cell migration
Cell Movement
Cytoskeleton
Extracellular matrix
Ezrin
Glioblastoma
Glioblastoma - pathology
Glycosaminoglycans
Humans
Hyaluronan Receptors - metabolism
Hyaluronic acid
Hyaluronic Acid - chemistry
hyaluronic acids
hydrogels
Integrins
Parenchyma
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Summary:Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient‐derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient‐derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient‐derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA‐engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44–HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA–CD44–ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain. Glioblastoma (GBM) tumors aggressively invade the brain and are highly lethal. Hyaluronic acid (HA), a polysaccharide ubiquitous in the brain extracellular matrix, is overexpressed in GBM tumors. Using patient‐derived GBM cells and engineered, 3D culture microenvironments, this work demonstrates a biphasic relationship between invasive activity and HA concentration that depends on phosphorylation of ezrin downstream of the CD44 receptor.
ISSN:2192-2640
2192-2659
DOI:10.1002/adhm.202203143