High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas. Ben-Men-1 cells grown in DMEM (11995-073), 20% FBS, 1% PenStrep were lentivirally transduced with pLJM1-GFP or pLJM1-VGLL4. RNASeq was done on positive clones. We then performed gene expression profiling analysis using data obtained from RNASeq of 3 GFP and 3 VGLL4 replicates