Abstract 2485: The Hippo downstream effector YAP promotes survival, radiation resistance and chromosome instability in medulloblastoma

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 2485
• Main Authors: Fernandez-L, Africa, Kenney, Anna M.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-2485

Abstract Medulloblastoma, the most common solid pediatric tumor, originates in the cerebellum during postnatal development. It is postulated that cerebellar granule neuron precursors (CGNPs) are cells-of-origin for certain classes of medulloblastomas. CGNPs require the mitogen/morphogen Shh to proliferate. We identified YAP as a new Shh target that promotes CGNP proliferation. YAP is a transcriptional co-activator negatively regulated by the Hippo pathway, a signaling cascade involved in organ size regulation and cell contact inhibition. We found YAP to be highly expressed in human and mouse Shh-driven medulloblastomas. Moreover, YAP was strikingly amplified in a subset of human medulloblastomas. YAP was localized to the peri-vascular niche where cancer stem cells have recently been described to reside in brain tumors. When we irradiated medulloblastoma-bearing mice, most of the cells in the tumor underwent apoptosis 6 hours after radiation. However, cells expressing YAP were resistant to radiation-induced apoptosis. These radiation-resistant cells have been described to have the ability to re-populate the tumor. In concordance with this, mouse medulloblastoma cells over-expressing YAP and injected in P0-P4 pups grow faster than those overexpressing GFP and give rise to more aggressive tumors. In vitro, YAP-overexpressing CGNPs and medulloblastoma cells produce higher levels of IGF2, which activates Akt and promotes their survival. 24 hours after radiation, YAP-overexpressing cells contain more damaged DNA; however, they skip the G2/M checkpoint and don't arrest despite the damage in their DNA. Our results indicate that YAP promotes both chromosome instability and survival of medulloblastoma cells, thus is a new attractive potential target for medulloblastoma therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2485. doi:10.1158/1538-7445.AM2011-2485