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

Author

Listed:
  • Hyun Jung Jun

    (Beth Israel Deaconess Medical Center)

  • Vicky A. Appleman

    (Beth Israel Deaconess Medical Center)

  • Hua-Jun Wu

    (Dana-Farber Cancer Institute
    Harvard T. H. Chan School of Public Health)

  • 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
    Harvard T. H. Chan School of Public Health)

  • 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
    Harvard T. H. Chan School of Public Health)

  • Timothy J. Mitchison

    (Harvard Medical School)

  • Al Charest

    (Beth Israel Deaconess Medical Center
    Harvard Medical School)

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.

Suggested Citation

  • 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 Bronis, 2018. "A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05036-4
    DOI: 10.1038/s41467-018-05036-4
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