Abstract 3352: The medulloblastoma oncogene Otx2 enhances migration and permits ectopic proliferation of neuronal progenitor cells of the cerebellum and brainstem

Abstract

Abstract Medulloblastoma is the most common malignant brain tumor in children. Despite a thorough understanding of the genetic underpinnings of this tumor, the pathogenesis of some variants of medulloblastoma, in particular the non-Shh/non-Wnt subtypes, is poorly understood. One of the most common genetic aberrations in non-Shh/non-Wnt medulloblastomas is copy number gain of the homeobox transcription factor OTX2. Here we have characterized mice engineered to ectopically express Otx2 in the hindbrain to identify the functional consequences of this subtype-specific genetic insult. Otx2 expression induced accumulation of proliferative hyperplasias in the cerebellar white matter and dorsal brainstem that were reminiscent of preneoplastic cells identified in other animal models of medulloblastoma. These hyperplasias were comprised of neuronal progenitor cells that had migrated away from their mitogenic niches. As animals reached adulthood, ectopic cells exited the cell cycle and differentiated, indicating that factors limiting proliferative lifespan prevented full transformation by Otx2. Comparison of the effect of Otx2 with activation of the Shh or Wnt pathways, which occur in distinct subtypes of medulloblastoma, revealed overlap of responsive cell types but distinct developmental processes involved. While activation of the Shh or Wnt pathways give rise to sustained proliferation of neuronal progenitor cells at their mitogenic niches, we found that Otx2 permitted or enhanced migration of these cells away from these niches and induced ectopic proliferation. These findings identify a role for Otx2 overexpression in altering spatiotemporal control of neuronal progenitor cell proliferation and implicate a relationship between the cells of origin of non-Shh/non-Wnt medulloblastomas and those of other medulloblastoma subtypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3352. doi:1538-7445.AM2012-3352