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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 languageEnglish (US)
Article number3116
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

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

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