Glioma Cell Migration on Three-dimensional 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 antimigratory targets could reduce glioma recurrence and improve therapeutic efficacy, but screens based on conventional migration assays are hampe...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2011-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558611800357 |
| _version_ | 1811297252439752704 |
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| author | Paula A. Agudelo-Garcia Jessica K. De Jesus Shante P. Williams Michal O. Nowicki Ennio Antonio Chiocca Sandya Liyanarachchi Pui-Kai Li John J. Lannutti Jed K. Johnson Sean E. Lawler Mariano S. Viapiano |
| author_facet | Paula A. Agudelo-Garcia Jessica K. De Jesus Shante P. Williams Michal O. Nowicki Ennio Antonio Chiocca Sandya Liyanarachchi Pui-Kai Li John J. Lannutti Jed K. Johnson Sean E. Lawler Mariano S. Viapiano |
| author_sort | Paula A. Agudelo-Garcia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T06:01:15Z |
| format | Article |
| id | doaj.art-70e89dedea95496eaed38ddd00abd254 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T06:01:15Z |
| publishDate | 2011-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-70e89dedea95496eaed38ddd00abd2542022-12-22T02:59:25ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022011-09-0113983184010.1593/neo.11612Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 SignalingPaula A. Agudelo-Garcia0Jessica K. De Jesus1Shante P. Williams2Michal O. Nowicki3Ennio Antonio Chiocca4Sandya Liyanarachchi5Pui-Kai Li6John J. Lannutti7Jed K. Johnson8Sean E. Lawler9Mariano S. Viapiano10Center for Molecular Neurobiology, The Ohio State University, Columbus, OH, USACenter for Molecular Neurobiology, The Ohio State University, Columbus, OH, USADardinger Neuro-Oncology Center, Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USADardinger Neuro-Oncology Center, Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USADardinger Neuro-Oncology Center, Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USADepartment of Biomedical Informatics, The Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USADivision of Medicinal Chemistry, The Ohio State University College of Pharmacy, Columbus, OH, USADepartment of Materials Science and Engineering, The Ohio State University College of Engineering, Columbus, OH, USADepartment of Materials Science and Engineering, The Ohio State University College of Engineering, Columbus, OH, USADardinger Neuro-Oncology Center, Department of Neurological Surgery, The Ohio State University Medical Center and James Cancer Hospital, Columbus, OH, USACenter for Molecular Neurobiology, The Ohio State University, Columbus, OH, USAA 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.http://www.sciencedirect.com/science/article/pii/S1476558611800357 |
| spellingShingle | Paula A. Agudelo-Garcia Jessica K. De Jesus Shante P. Williams Michal O. Nowicki Ennio Antonio Chiocca Sandya Liyanarachchi Pui-Kai Li John J. Lannutti Jed K. Johnson Sean E. Lawler Mariano S. Viapiano Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling Neoplasia: An International Journal for Oncology Research |
| title | Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling |
| title_full | Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling |
| title_fullStr | Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling |
| title_full_unstemmed | Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling |
| title_short | Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling |
| title_sort | glioma cell migration on three dimensional nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of stat3 signaling |
| url | http://www.sciencedirect.com/science/article/pii/S1476558611800357 |
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