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

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 PD...

Descripción completa

Detalles Bibliográficos
Autores principales: 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., Charest, Al
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078993/
https://www.ncbi.nlm.nih.gov/pubmed/30082792
http://dx.doi.org/10.1038/s41467-018-05036-4
Descripción
Sumario: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.

Ejemplares similares