YAP1 drives ependymoma-like tumor formation in the brain.

Ependymoma is the third most common pediatric brain cancer. YAP1 gene fusions have been observed in a subset of pediatric ependymomas. Here we show that increased YAP1 activity has a causative role in ependymoma-like tumor formation. YAP1 protein is strongly expressed and localized in the nucleus in a subset of human ependymomas. In the developing brain, YAP1 expression is normally found in subventricular zone neural progenitor cells, and NEX/NeuroD6-Cre induced conditional expression of active nuclear YAP1 (YAP1-5SAnls) is sufficient to drive brain tumor formation. YAP1 drives tumor formation by maintaining a nestin positive neural stem cell-like specification and preventing hippocampal neuronal differentiation. Dual conditional deletion of LATS1 and LATS2 kinases in the NEX-Cre lineage also generates similar tumors. Genetic rescue experiments in mice show that either YAP1 or its homolog TAZ can drive tumor formation downstream of LATS1/2 kinases. YAP1/TAZ activity causes tumors that display histologic and molecular characteristics of ependymoma, including ultrastructural features microvilli and tight junctions. Our results show that disruption of YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumors. Citation Format: Noreen Eder, Marie-Charlotte Dolmart, Suzanne Claxton, Jennifer Cotton, Jun-Hao Mao, Bram Snijders, Federico Roncaroli, Barry Thompson, Sila Ultanir. YAP1 drives ependymoma-like tumor formation in the brain [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A01.