Molecular Mechanism of Targeting Epithelial Membrane Protein-2 in Malignant Meningiomas

INTRODUCTION: Meningiomas compose approximately one third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%. METHODS: In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and have analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay. RESULTS: Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p < 0.001). Moreover, cellular migration and invasion regulated by EMP2 was tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti- EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2 mediated signal transduction (p = 0.0031). CONCLUSIONS: Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefit in malignant meningiomas.