SHP-2-upregulated ZEB1 is important for PDGFRα-driven glioma epithelial-mesenchymal transition and invasion in mice and humans

Gliomas are highly malignant brain tumors that are highly invasive and resistant to conventional therapy. Receptor tyrosine kinases (RTKs) such as PDGFR alpha (platelet-derived growth factor receptor-alpha), which show frequent aberrant activation in gliomas, are associated with a process of epithelial-mesenchymal transition (EMT), a cellular alteration that confers a more invasive and drug-resistant phenotype. Although this phenomenon is well documented in human cancers, the processes by which RTKs including PDGFR alpha mediate EMT are largely unknown. Here, we report that SHP-2 (encoded by PTPN11) upregulates an EMT inducer, ZEB1, to mediate PDGFR alpha-driven glioma EMT, invasion and growth in glioma cell lines and patient-derived glioma stem cells (GSCs) using cell culture and orthotopic xenograft models. ZEB1 and activated PDGFR alpha were coexpressed in invasive regions of mouse glioma xenografts and clinical glioma specimens. Glioma patients with high levels of both phospho-PDGFR alpha (p-PDGFR alpha) and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFR alpha and ZEB1. Knockdown of ZEB1 inhibited PDGFA/PDGFR alpha-stimulated glioma EMT, tumor growth and invasion in glioma cell lines and patient-derived GSCs. PDGFR alpha mutant deficient of SHP2 binding (PDGFR alpha-F720) or phosphoinositide 3-kinase (PI3K) binding (PDGFR alpha-F731/42), knockdown of SHP2 or treatments of pharmacological inhibitor for PDGFR alpha-signaling effectors attenuated PDGFA/PDGFR alpha-stimulated ZEB1 expression, cell migration and GSC proliferation. Importantly, SHP-2 acts together with PI3K/AKT to regulate a ZEB1-miR-200 feedback loop in PDGFR alpha-driven gliomas. Taken together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFR alpha-driven glioma EMT, invasiveness and growth, suggesting that ZEB1 is a promising therapeutic target for treating gliomas with high PDGFR alpha activation.