A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine
Autor: | Timothy J. Mitchison, Al Charest, Keith L. Ligon, Ennio Antonio Chiocca, Aron Gyuris, Alan T. Yeo, Franziska Michor, Jann N. Sarkaria, Ichiro Nakano, Hua-Jun Wu, Agnieszka Bronisz, Steve P. Gygi, Roderick T. Bronson, Bethany Delcuze, Charlotte E. Lee, Steve Woolfenden, Javier Pineda, Hyun Jung Jun, Christopher M. Rose, Haihao Zhu, Vicky A. Appleman |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Proteomics General Physics and Astronomy Apoptosis Mice 0302 clinical medicine Cytotoxic T cell Phosphorylation lcsh:Science Cells Cultured Multidisciplinary Chemistry Cell Cycle Cell cycle Magnetic Resonance Imaging 3. Good health Vinblastine Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Female Signal transduction medicine.drug Signal Transduction Cell Survival Science Antineoplastic Agents Breast Neoplasms General Biochemistry Genetics and Molecular Biology Article Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences medicine Animals Humans Autocrine signalling Computational Biology General Chemistry nervous system diseases Disease Models Animal 030104 developmental biology Drug Resistance Neoplasm Genetically Engineered Mouse Cancer research Stathmin lcsh:Q Glioblastoma Neoplasm Transplantation |
Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. |
Databáze: | OpenAIRE |
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