Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

Nat Cell Biol. 2016 Apr;18(4):418-30. doi: 10.1038/ncb3327. Epub 2016 Mar 21.

Abstract

Aberrant Notch signalling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly paediatric brain neoplasms. We developed animal models of CP tumours, by inducing sustained expression of Notch1, that recapitulate properties of human CP tumours with aberrant NOTCH signalling. Whole-transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate differentiation. A Shh-driven signalling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from monociliated progenitors in the roof plate characterized by elevated Notch signalling. Abnormal SHH signalling and distinct ciliogenesis are detected in human CP tumours, suggesting the SHH pathway and cilia differentiation as potential therapeutic avenues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Proliferation / genetics*
  • Choroid Plexus / metabolism
  • Choroid Plexus / pathology
  • Choroid Plexus / ultrastructure
  • Choroid Plexus Neoplasms / genetics*
  • Choroid Plexus Neoplasms / metabolism
  • Choroid Plexus Neoplasms / pathology
  • Cilia / metabolism
  • Cilia / ultrastructure
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Oligonucleotide Array Sequence Analysis
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Tumor Cells, Cultured
  • Tumor Microenvironment / genetics

Substances

  • Hedgehog Proteins
  • Receptor, Notch1

Associated data

  • GEO/GSE77123