Work

Modl-36. Expression of Yap1-maml2 and Constitutively Active Yap1 Drive the Formation of Meningioma-like Tumors in Mice That Resemble Nf2-mutant Meningiomas

Year: 2022

Type: article

Abstract: YAP1 is a transcriptional co-activator and oncogene under the control of the Hippo Signaling Pathway. Functional inactivation of Hippo Pathway tumor suppressors, including NF2, are frequent events in human cancers. Meningiomas are the most common primary brain tumors, and a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 gene copy, implicating oncogenic YAP activity in the pathobiology of almost half of these tumors. An alternate type of activating YAP1 mutation are YAP1 gene fusions that have been identified in several cancer subtypes. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that the expression profile of human YAP1-MAML2-positive pediatric meningiomas resembles that of the common NF2-mutant meningiomas based on global and YAP-related gene expression signatures. We then use the RCAS/tv-a system for postnatal gene transfer and show that the intracranial expression of YAP1-MAML2 in neonatal mice results in the formation of meningioma-like tumors that exert a similar gene expression pattern as seen in human YAP1 fusion-positive and NF2-mutant meningiomas and regulate classical YAP1 target genes. We demonstrate that YAP1-MAML2 exerts oncogenic YAP activity that is resistant to inhibitory Hippo pathway signaling and relies on the interaction with TEAD transcription factors. Pharmacological disruption of this interaction is sufficient to inhibit the viability of YAP1-MAML2-expressing mouse tumors ex vivo. Finally, we show that constitutively active YAP1 (S127/397A-YAP1) is also sufficient to cause the formation of similar meningioma-like tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a sufficient oncogenic driver in YAP1-MAML2 fusion-positive meningiomas, which mimic NF2-mutant meningiomas, and highlight TEAD-dependent YAP activity as a potential therapeutic target in these tumors.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noac209.1163