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A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PD...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2018
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078993/ https://www.ncbi.nlm.nih.gov/pubmed/30082792 http://dx.doi.org/10.1038/s41467-018-05036-4 |
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| author | Jun, Hyun Jung Appleman, Vicky A. Wu, Hua-Jun Rose, Christopher M. Pineda, Javier J. Yeo, Alan T. Delcuze, Bethany Lee, Charlotte Gyuris, Aron Zhu, Haihao Woolfenden, Steve Bronisz, Agnieszka Nakano, Ichiro Chiocca, Ennio A. Bronson, Roderick T. Ligon, Keith L. Sarkaria, Jann N. Gygi, Steve P. Michor, Franziska Mitchison, Timothy J. Charest, Al |
| author_facet | Jun, Hyun Jung Appleman, Vicky A. Wu, Hua-Jun Rose, Christopher M. Pineda, Javier J. Yeo, Alan T. Delcuze, Bethany Lee, Charlotte Gyuris, Aron Zhu, Haihao Woolfenden, Steve Bronisz, Agnieszka Nakano, Ichiro Chiocca, Ennio A. Bronson, Roderick T. Ligon, Keith L. Sarkaria, Jann N. Gygi, Steve P. Michor, Franziska Mitchison, Timothy J. Charest, Al |
| author_sort | Jun, Hyun Jung |
| collection | PubMed |
| description | Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM. |
| format | Online Article Text |
| id | pubmed-6078993 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2018 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-60789932018-08-08 A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine Jun, Hyun Jung Appleman, Vicky A. Wu, Hua-Jun Rose, Christopher M. Pineda, Javier J. Yeo, Alan T. Delcuze, Bethany Lee, Charlotte Gyuris, Aron Zhu, Haihao Woolfenden, Steve Bronisz, Agnieszka Nakano, Ichiro Chiocca, Ennio A. Bronson, Roderick T. Ligon, Keith L. Sarkaria, Jann N. Gygi, Steve P. Michor, Franziska Mitchison, Timothy J. Charest, Al Nat Commun Article Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM. Nature Publishing Group UK 2018-08-06 /pmc/articles/PMC6078993/ /pubmed/30082792 http://dx.doi.org/10.1038/s41467-018-05036-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article Jun, Hyun Jung Appleman, Vicky A. Wu, Hua-Jun Rose, Christopher M. Pineda, Javier J. Yeo, Alan T. Delcuze, Bethany Lee, Charlotte Gyuris, Aron Zhu, Haihao Woolfenden, Steve Bronisz, Agnieszka Nakano, Ichiro Chiocca, Ennio A. Bronson, Roderick T. Ligon, Keith L. Sarkaria, Jann N. Gygi, Steve P. Michor, Franziska Mitchison, Timothy J. Charest, Al A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title | A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title_full | A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title_fullStr | A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title_full_unstemmed | A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title_short | A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| title_sort | pdgfrα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078993/ https://www.ncbi.nlm.nih.gov/pubmed/30082792 http://dx.doi.org/10.1038/s41467-018-05036-4 |
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