GSE61528
YAP mediates tumorigenesis in neurofibromatosis type 2 through a COX2-EGFR signaling axis
The Hippo-YAP signaling pathway has emerged as a major driver of tumorigenesis in a wide spectrum of human cancers.  YAP functions as a transcriptional activator and while details of YAP regulation are emerging at a fast pace, it remains unknown what downstream targets are critical for YAP oncogenic functions. To establish the mechanisms involved and identify disease-relevant targets we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. YAP function is required in NF2-null Schwann cells to promote cell survival and for tumor growth, in vivo. Moreover, YAP promotes transcription of several targets including Prostaglandin-endoperoxide synthase 2 (PTGS2), which controls production of prostaglandin E2 (PGE2) and amphiregulin (AREG), a member of the epidermal growth factor family. Both AREG and PGE2 converge to activate survival signaling through EGFR, in a Src-dependent manner, thus promoting cell survival. Importantly, treatment with the COX2 inhibitor celecoxib significantly repressed the growth of NF2-null Schwann cells in vitro and tumor growth in a mouse model of NF2-associated schwnnoma. Overall design: YAP-dependent differential gene expression was assessed by RNA-Seq on Nf2-null Schwann cells treated with 1) Control siRNA, or 2) YAP pooled siRNA for 48 hours.