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Dual and opposing roles of primary cilia in medulloblastoma development

Authors
Journal
Nature Medicine
1078-8956
Publisher
Nature Publishing Group
Publication Date
Volume
15
Issue
9
Identifiers
DOI: 10.1038/nm.2020
Keywords
  • Article
Disciplines
  • Medicine

Abstract

Recent work has shown that primary cilia are essential for Hh signaling during mammalian development1–9. It is also known that aberrant Hedgehog (Hh) signaling can lead to cancer10, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children11,12. The primary cilium and Hh signaling are required for GNPs proliferation8,13–16. We asked whether primary cilia in GNPs play a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma growth when this tumor was driven by a constitutively active Smoothened (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active Gli2, a downstream transcription factor. Thus, primary cilia are required for, or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, presence or absence of cilia were associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling, but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.

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