Format

Send to

Choose Destination
Nat Commun. 2018 Aug 6;9(1):3116. doi: 10.1038/s41467-018-05036-4.

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

Author information

1
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
3
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, 02215, USA.
5
Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
6
Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, 02111, USA.
7
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
8
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
9
Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35243, USA.
10
Rodent Histopathology Core, Dana-Farber/Harvard Cancer Center, Boston, MA, 02215, USA.
11
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
12
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55902, USA.
13
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. acharest@bidmc.harvard.edu.
14
Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. acharest@bidmc.harvard.edu.

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.

PMID:
30082792
PMCID:
PMC6078993
DOI:
10.1038/s41467-018-05036-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center