A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine

Hyun Jung Jun; Vicky A. Appleman; Hua Jun Wu; Christopher M. Rose; Javier J. Pineda; Alan T. Yeo; Bethany Delcuze; Charlotte Lee; Aron Gyuris; Haihao Zhu; Steve Woolfenden; Agnieszka Bronisz; Ichiro Nakano; Ennio A. Chiocca; Roderick T. Bronson; Keith L. Ligon; Jann N. Sarkaria; Steve P. Gygi; Franziska Michor; Timothy J. Mitchison; Al Charest

doi:10.1038/s41467-018-05036-4

A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine

Hyun Jung Jun, Vicky A. Appleman, Hua Jun Wu, Christopher M. Rose, Javier J. Pineda, Alan T. Yeo, Bethany Delcuze, Charlotte Lee, Aron Gyuris, Haihao Zhu, Steve Woolfenden, Agnieszka Bronisz, Ichiro Nakano, Ennio A. Chiocca, Roderick T. Bronson, Keith L. Ligon, Jann N. Sarkaria, Steve P. Gygi, Franziska Michor, Timothy J. MitchisonAl Charest

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English (US)
Article number	3116
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05036-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Jun, H. J., Appleman, V. A., Wu, H. J., Rose, C. M., Pineda, J. J., Yeo, A. T., Delcuze, B., Lee, C., Gyuris, A., Zhu, H., Woolfenden, S., Bronisz, A., Nakano, I., Chiocca, E. A., Bronson, R. T., Ligon, K. L., Sarkaria, J. N., Gygi, S. P., Michor, F., ... Charest, A. (2018). A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine. Nature communications, 9(1), [3116]. https://doi.org/10.1038/s41467-018-05036-4

Jun, HJ, Appleman, VA, Wu, HJ, Rose, CM, Pineda, JJ, Yeo, AT, Delcuze, B, Lee, C, Gyuris, A, Zhu, H, Woolfenden, S, Bronisz, A, Nakano, I, Chiocca, EA, Bronson, RT, Ligon, KL, Sarkaria, JN, Gygi, SP, Michor, F, Mitchison, TJ & Charest, A 2018, 'A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine', Nature communications, vol. 9, no. 1, 3116. https://doi.org/10.1038/s41467-018-05036-4

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title = "A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine",

abstract = "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.",

author = "Jun, {Hyun Jung} and Appleman, {Vicky A.} and Wu, {Hua Jun} and Rose, {Christopher M.} and Pineda, {Javier J.} and Yeo, {Alan T.} and Bethany Delcuze and Charlotte Lee and Aron Gyuris and Haihao Zhu and Steve Woolfenden and Agnieszka Bronisz and Ichiro Nakano and Chiocca, {Ennio A.} and Bronson, {Roderick T.} and Ligon, {Keith L.} and Sarkaria, {Jann N.} and Gygi, {Steve P.} and Franziska Michor and Mitchison, {Timothy J.} and Al Charest",

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AU - Rose, Christopher M.

AU - Pineda, Javier J.

AU - Yeo, Alan T.

AU - Delcuze, Bethany

AU - Lee, Charlotte

AU - Gyuris, Aron

AU - Zhu, Haihao

AU - Woolfenden, Steve

AU - Bronisz, Agnieszka

AU - Nakano, Ichiro

AU - Chiocca, Ennio A.

AU - Bronson, Roderick T.

AU - Ligon, Keith L.

AU - Sarkaria, Jann N.

AU - Gygi, Steve P.

AU - Michor, Franziska

AU - Mitchison, Timothy J.

AU - Charest, Al

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N2 - 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.

AB - 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.

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A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine

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