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We hypothesized that inhibiting CS\u2010GAG signaling in the TME would stem GBM invasion. Rat F98 GBM cells demonstrated enhanced preferential cell invasion into oversulfated 3\u2010dimensional composite of CSA and CS\u2010E [4\u2010 and 4,6\u2010sulfated CS\u2010GAG (COMP)] matrices compared with monosulfated (4\u2010sulfated) and unsulfated hyaluronic acid matrices in microfluidics\u2010based choice assays, which is likely influenced by differential GAG receptor binding specificities. Both F98 and human patient\u2010derived glioma stem cells (GSCs) demonstrated a high degree of colocalization of the GSC marker CD133 and CSPGs. The small molecule sulfated GAG antagonist bis\u20102\u2010methyl\u20104\u2010amino\u2010quinolyl\u20106\u2010carbamide (surfen) reduced invasion and focal adhesions in F98 cells encapsulated in COMP matrices and blocked CD133 and antichondroitin sulfate antibody (CS\u201056) detection of respective antigens in F98 cells and human GSCs. Surfen\u2010treated F98 cells down\u2010regulated CSPG\u2010binding receptor transcripts and protein, as well as total and activated ERK and protein kinase B. Lastly, rats induced with frontal lobe tumors and treated with a single intratumoral dose of surfen demonstrated reduced tumor burden and spread compared with untreated controls. These results present a first demonstration of surfen as an inhibitor of sulfated GAG signaling to stem GBM invasion.\u2014Logun, M. T., Wynens, K. E., Simchick, G., Zhao, W., Mao, L., Zhao, Q., Mukherjee, S., Brat, D. J., Karumbaiah, L. Surfen\u2010mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion. FASEB J. 33, 11973\u201011992 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802610rr","type":"journal-article","created":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T17:45:37Z","timestamp":1565372737000},"page":"11973-11992","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Surfen\u2010mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion"],"prefix":"10.1096","volume":"33","author":[{"given":"Meghan T.","family":"Logun","sequence":"first","affiliation":[{"name":"Regenerative Bioscience Center University of Georgia Athens Georgia USA"},{"name":"Division of Neuroscience Biomedical and Health Sciences Institute University of Georgia Athens Georgia USA"},{"name":"Edgar L. 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