Dual and opposing roles of primary cilia in medulloblastoma development

Abstract

These two studies show that primary cilia can either mediate or suppress tumorigenesis in models of basal cell carcinoma and medulloblastoma, respectively, depending on the nature of the initial oncogenic event ( pages 994–996 ) and ( pages 1055–1061 ). Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development1,2,3,4,5,6,7,8,9. It is also known that aberrant 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 GNP proliferation8,12,13,14,15. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was 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.