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

• Published in: Nature communications Vol. 9; no. 1; pp. 3116 - 13
• Main 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., Charest, Al
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/39; 631/67/1059/99; 631/67/1922; 631/67/70; 82/58; 96; 96/95; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Autocrine signalling; Biology; Brain; Brain cancer; Brain research; Breast Neoplasms - metabolism; Cancer; Cancer therapies; Cell Cycle; Cell Survival; Cells, Cultured; Computational Biology; Cytotoxicity; Diet; Disease Models, Animal; Drug Resistance, Neoplasm; Drugs; Female; Gene Expression Regulation, Neoplastic; Genes; Genetic engineering; Glioblastoma; Glioblastoma - metabolism; Histopathology; Humanities and Social Sciences; Humans; Kinases; Ligands; Magnetic Resonance Imaging; Male; Medical research; Medical schools; Mice; multidisciplinary; Neoplasm Transplantation; Neurosurgery; Oncology; Phosphorylation; Polymerization; Proteins; Proteomics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Science; Science (multidisciplinary); Sensitivity; Signal Transduction; Stathmin - metabolism; Toxicity; Tubulin; Tumorigenesis; Tumors; Vinblastine; Vinblastine - pharmacology; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05036-4

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.