Glioma cell migration on 3D nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of STAT3 signaling
A hallmark of malignant gliomas is their ability to disperse through neural tissue, leading to long-term failure of all known therapies. Identifying new anti-migratory targets could reduce glioma recurrence and improve therapeutic efficacy, but screens based on conventional migration assays are hamp...
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| Published in: | Neoplasia (New York, N.Y.) Vol. 13; no. 9 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
01-09-2011
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| Online Access: | Get full text |
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| Summary: | A hallmark of malignant gliomas is their ability to disperse through neural tissue, leading to long-term failure of all known therapies. Identifying new anti-migratory 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 sub-micron 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 sub-toxic concentrations. Remarkably, these inhibitors were ineffective when tested at the same concentrations in a conventional 2D 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 anti-migratory strategies not disclosed by other in vitro models. |
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| Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-1 |
| ISSN: | 1522-8002 |