Molecular Bases of Disease
Epithelial Membrane Protein-2 (EMP2) Activates Src Protein and Is a Novel Therapeutic Target for Glioblastoma*

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Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvβ3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Cell Invasion
Glioblastoma
Immunotherapy
Tetraspanins
Tumor Marker
EMP2

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*

This work was supported, in whole or in part, by National Institutes of Health Grants CA-86366 from NCI Early Detection Research Network (to L. G.), R01 CA163971 (to M. W.), CA 143931CDU/UCLA Cancer Center Partnership U54 (to M. W.), Grant P30 CA016042 to Jonsson Comprehensive Cancer Center, and Grant 5P30 AI028697 from CFAR. This work was also supported by a Stein Oppenheimer seed grant (to L. G.).

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Both authors contributed equally to this work.