Abstract LB-385: The Hippo pathway component YAP1 promotes cerebellar precursor survival after irradiation and can accelerate medulloblastoma onset

Medulloblastoma is the most common malignant solid tumor in children. These tumors arise in the developing cerebellum, a region of the brain that undergoes rapid expansion after birth. Current treatments for medulloblastoma include radiation, surgery and chemotherapy, all of which are associated with devastating physical and mental side effects in long-term survivors. Recently, cells within medulloblastomas that survive radiation treatment and can repopulate the tumors post-radiation have been identified. These cells reside in regions adjacent to blood vessels, and their post-radiation survival is promoted by PI3 kinase pathway activity. Ideal medulloblastoma therapies will attack the tumors and eliminate the tumor re-initiating cells but spare the rest of the brain. We have recently published that the oncogenic transcriptional co-activator YAP1, which is negatively regulated by the Hippo pathway, is up regulated and amplified in a subset of human medulloblastomas with aberrant Sonic hedgehog (Shh) signaling. YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly-growing tumor cells. We report here that YAP1 is actively involved in survival post-irradiation. CGNPs that over-express YAP1 in vitro proliferate more and present less apoptosis after irradiation than those over-expressing GFP. Among YAP1 target genes in CGNPs we found Securin, which, apart from its known role in mitosis, it has been shown to have roles in survival after DNA damage. We also found Securin highly expressed in human and mouse medulloblastomas. Moreover, injection of YAP 1 over-expressing medulloblastoma cells in postnatal day 4 wild type mice accelerate medulloblastoma onset compared to GFP over-expressing cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-385.