Abstract 695: SHP-2-upregulated ZEB1 is important for PDGFRá-driven glioma epithelial-mesenchymal transition and invasion in mice and humans

Abstract

Abstract A critical clinical challenge in glioblastoma therapy is robust tumor growth and invasion driven by aberrant activation of oncogenic tyrosine receptor kinases (RTKs) including PDGFRá. Here, we report that a SHP-2-upregulated epithelial-mesenchymal transition (EMT)-inducer, ZEB1 is important for PDGFRá-driven glioma EMT, invasion and glioma stem cell renewal in mice and humans. ZEB1 and activated PDGFRá were co-expressed in invasive regions of mouse glioma xenografts and human clinical glioma specimens. Glioma patients with high levels of both p-PDGFRá and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRá and ZEB1. Knockdown of ZEB1 inhibited PDGF-A/PDGFRá-stimulated glioma EMT, tumor growth, invasion and glioma stem cell renewal. PDGFRá mutant deficient of SHP-2 binding (PDGFRá-F720) or PI3K binding (PDGFRá-F731/42), knockdown of SHP-2 or treatments of pharmacological inhibitor for PDGFRá-signaling effectors attenuated PDGF-A/PDGFRá-stimulated ZEB1 expression, cell migration and glioma stem cell proliferation. Importantly, SHP-2 acts together with PI3K/Akt to regulate a ZEB1-miR-200 feedback loop in PDGFRá-driven gliomas. Together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRá-driven glioma EMT, invasion and glioma stem cell renewal, suggesting that ZEB1 as a potential therapeutic target for human gliomas with high PDGFRá activation. Citation Format: Lei Zhang, Weiwei Zhang, Yanxin Li, Zuoqing Li, Yinfang Wang, Lina Song, Deguan Lv, Ichiro Nakano, Bo Hu, Shi-Yuan Cheng, Haizhong Feng. SHP-2-upregulated ZEB1 is important for PDGFRá-driven glioma epithelial-mesenchymal transition and invasion in mice and humans. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 695.