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
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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