We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine.
- Authors
Jun, Hyun Jung; Appleman, Vicky A.; Wu, Hua-Jun; Rose, Christopher M.; Pineda, Javier J.; Yeo, Alan T.; Delcuze, Bethany; Lee, Charlotte; Gyuris, Aron; Zhu, Haihao; Woolfenden, Steve; Bronisz, Agnieszka; Nakano, Ichiro; Chiocca, Ennio A.; Bronson, Roderick T.; Ligon, Keith L.; Sarkaria, Jann N.; Gygi, Steve P.; Michor, Franziska; Mitchison, Timothy J.
- 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. Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα regulated-protein involved in the response to vinstabline.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05036-4