title: Glioma cell migration on three-dimensional nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of STAT3 signaling.
abstract: A hallmark of malignant gliomas is their ability to disperse through neural tissue, leading to long-term failure of all known therapies. Identifying new antimigratory targets could reduce glioma recurrence and improve therapeutic efficacy, but screens based on conventional migration assays are hampered by the limited ability of these assays to reproduce native cell motility. Here, we have analyzed the motility, gene expression, and sensitivity to migration inhibitors of glioma cells cultured on scaffolds formed by submicron-sized fibers (nanofibers) mimicking the neural topography. Glioma cells cultured on aligned nanofiber scaffolds reproduced the elongated morphology of cells migrating in white matter tissue and were highly sensitive to myosin II inhibition but only moderately affected by stress fiber disruption. In contrast, the same cells displayed a flat morphology and opposite sensitivity to myosin II and actin inhibition when cultured on conventional tissue culture polystyrene. Gene expression analysis indicated a correlation between migration on aligned nanofibers and increased STAT3 signaling, a known driver of glioma progression. Accordingly, cell migration out of glioblastoma-derived neurospheres and tumor explants was reduced by STAT3 inhibitors at subtoxic concentrations. Remarkably, these inhibitors were ineffective when tested at the same concentrations in a conventional two-dimensional migration assay. We conclude that migration of glioma cells is regulated by topographical cues that affect cell adhesion and gene expression. Cell migration analysis using nanofiber scaffolds could be used to reproduce native mechanisms of migration and to identify antimigratory strategies not disclosed by other in vitro models.
authors.affiliation: Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Agudelo-Garcia
authors.forename: Jessica K
authors.initials: JK
authors.lastname: De Jesus
authors.forename: Shante P
authors.initials: SP
authors.lastname: Williams
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Ennio Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: John J
authors.initials: JJ
authors.lastname: Lannutti
authors.forename: Jed K
authors.initials: JK
authors.lastname: Johnson
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Mariano S
authors.initials: MS
authors.lastname: Viapiano
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D015870:Gene Expression; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D024462:Myosin Type II / Q000037:antagonists & inhibitors; D057139:Nanofibers; D009361:Neoplasm Invasiveness; D011137:Polystyrenes / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D054457:Tissue Scaffolds; D014183:Transplantation, Heterologous
chemical_list: D000199:Actins; D000880:Anthraquinones; D003499:Cyclic S-Oxides; C549232:LLL12 compound; D011137:Polystyrenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; C517409:stattic; D024462:Myosin Type II