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 and Al Charest ()
Additional contact information
Hyun Jung Jun: Beth Israel Deaconess Medical Center
Vicky A. Appleman: Beth Israel Deaconess Medical Center
Hua-Jun Wu: Dana-Farber Cancer Institute
Christopher M. Rose: Harvard Medical School
Javier J. Pineda: Harvard Medical School
Alan T. Yeo: Tufts University School of Medicine
Bethany Delcuze: Tufts University School of Medicine
Charlotte Lee: Dana-Farber Cancer Institute
Aron Gyuris: Beth Israel Deaconess Medical Center
Haihao Zhu: Tufts Medical Center
Steve Woolfenden: Tufts Medical Center
Agnieszka Bronisz: Harvard Medical School
Ichiro Nakano: University of Alabama at Birmingham
Ennio A. Chiocca: Harvard Medical School
Roderick T. Bronson: Dana-Farber/Harvard Cancer Center
Keith L. Ligon: Dana-Farber Cancer Institute
Jann N. Sarkaria: Mayo Clinic
Steve P. Gygi: Harvard Medical School
Franziska Michor: Dana-Farber Cancer Institute
Timothy J. Mitchison: Harvard Medical School
Al Charest: Beth Israel Deaconess Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05036-4

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