Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

University of California, Department of Neurology, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Cancer cell (Impact Factor: 23.89). 05/2012; 21(5):601-13. DOI: 10.1016/j.ccr.2012.04.012
Source: PubMed

ABSTRACT The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.

Download full-text


Available from: Matt Grimmer, Jul 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain tumors are the most common solid tumors in children. Pediatric high-grade glioma (HGG) accounts for ∼8-12 % of these brain tumors and is a devastating disease as 70-90 % of patients die within 2 years of diagnosis. The failure to advance therapy for these children over the last 30 years is largely due to limited knowledge of the molecular basis for these tumors and a lack of disease models. Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying either K27M or G34R/V mutations. Although mutations in many chromatin modifiers have been identified in cancer, this was the first demonstration that histone mutations may be drivers of disease. Subsequent studies have identified high-frequency mutation of histone H3 to K36M in chondroblastomas and to G34W/L in giant cell tumors of bone, which are diseases of adolescents and young adults. Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3. Here, we review the peculiar characteristics of histone H3.3 and use this information as a backdrop to highlight current thinking about how the identified mutations may contribute to disease development.
    Chromosoma 03/2015; 124(2). DOI:10.1007/s00412-015-0510-4 · 3.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of progenitor's identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role in the origin and maintenance of the subpopulation of cancer stem cells in these tumors.
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: It has been more that 20 years since the first SOX genes were discovered. Twenty SOX genes have now been identified in mammals and classified into groups with respect to protein identity. SOX family genes code for transcription factors that either activate or repress lineage-specific genes during embryonic development. Furthermore, SOX genes are altered in human genetic syndromes and malignancies, highlighting their involvement in development. AREAS COVERED: This paper reviews the role of SOX genes in embryonic development and human diseases, and describe their involvement in human cancers and possible use in cancer therapeutics. EXPERT OPINION: Since most SOX genes behave as oncogenes in many human cancers, their targeting has great therapeutic potential. However, novel specific therapies such as those recently developed against growth factor receptors based on monoclonal antibodies, small inhibitors and even small interfering RNA strategies are difficult to implement for transcriptional factors. Novel strategies are being developed to overcome some of these obstacles. Alternative approaches could indirectly tackle altered SOX genes by exploiting the related molecular networks.
    Expert Opinion on Therapeutic Targets 07/2012; 16(9):903-19. DOI:10.1517/14728222.2012.709239 · 4.90 Impact Factor