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A PDGFR?-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine.

ABSTRACT: Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFR? 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 PDGFR?, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFR? phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFR?-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 PDGFR? activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.

SUBMITTER: Jun HJ 

PROVIDER: S-EPMC6078993 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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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  ...[more]

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