Article | Published:

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

Nature Cell Biology volume 18, pages 418430 (2016) | Download Citation

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.

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Acknowledgements

We thank all members of the laboratory for helpful discussions. We are grateful to K. Millen (Seattle Children’s Hospital Research Institute, USA), J. Kim (University of Texas Southwestern Medical Center, USA) and R. Kageyama (Institute for Virus Research Kyoto University, Japan) for providing the Lmx1a–Cre transgenic mouse strain, Smo antibody, and Hes1 antibodies, respectively, and C. Eberhart (Johns Hopkins University School of Medicine, USA), M. Taylor (The Hospital for Sick Children, Canada) and S. Santagata (Boston Children’s Hospital, USA) for providing human CP tumour samples. We wish to acknowledge the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by b.r.a.i.n child and Meagan’s Walk. We are indebted to C. Evans, A. Kelsch and E. Grandprey for excellent technical assistance. We thank W.K. Miskimins and K. Surendran for helpful suggestions, and J. Tao and D. Maher for critical reading of the manuscript and helpful discussions. This project is supported by: Boston Children’s Hospital IDDRC P30 HD18655, Sanford Research, and Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under grant number 5P20GM103548 (Cancer), which also supports Cores at Sanford Research together with NIH grant 1P20GM103620-01A1 (Pediatrics). The RNA In Situ Hybridization Core facility at Baylor College of Medicine is supported by a Shared Instrumentation grant from the NIH (1S10OD016167). Additional support was provided by the National Brain Tumor Society (R.J.W.-R.).

Author information

Affiliations

  1. Children’s Health Research Center, Sanford Research, 2301 E 60th Street North, Sioux Falls, South Dakota 57104, USA

    • Li Li
    • , Katie B. Grausam
    •  & Haotian Zhao
  2. Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 E. Clark Street, Vermillion, South Dakota 57069, USA

    • Katie B. Grausam
    •  & Haotian Zhao
  3. Tumor Initiation and Maintenance Programme, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

    • Jun Wang
    •  & Robert J. Wechsler-Reya
  4. Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • Melody P. Lun
    • , Hart G. W. Lidov
    • , Monica L. Calicchio
    •  & Maria K. Lehtinen
  5. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA

    • Melody P. Lun
  6. Center for Neuropathology and Prion Research, Ludwig-Maximilans-University, 81377 Munich, Germany

    • Jasmin Ohli
    •  & Ulrich Schüller
  7. Department of Biology, University of South Dakota, 414 E. Clark Street, Vermillion, South Dakota 57069, USA

    • Erliang Zeng
  8. Department of Computer Science, University of South Dakota, 414 E. Clark Street, Vermillion, South Dakota 57069, USA

    • Erliang Zeng
  9. Department of Biochemistry and Molecular Biology, Mayo Clinic (Guggenheim-14), 200 First Street SW., Rochester, Minnesota 55905, USA

    • Jeffrey L. Salisbury
  10. Microscopy and Cell Analysis Core, Mayo Clinic (Guggenheim-14), 200 First Street SW., Rochester, Minnesota 55905, USA

    • Jeffrey L. Salisbury
  11. Cancer Biology Research Center, Sanford Research, 2301 E 60th Street North, Sioux Falls, South Dakota 57104, USA

    • Haotian Zhao
  12. Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, 1400 W 22nd Street, Sioux Falls, South Dakota 57105, USA

    • Haotian Zhao
  13. Department of Chemistry and Biochemistry, South Dakota State University, Avera Health Science Center (SAV) 131, Brookings, South Dakota 57007, USA

    • Haotian Zhao

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Contributions

L.L. and H.Z. conceived and planned the project, and wrote the manuscript. H.G.W.L. and M.L.C. reviewed diagnoses of human tissue samples. J.W., J.O., R.J.W.-R. and U.S. analysed morphological characters and gene expression patterns of human tumour samples. M.P.L. and M.K.L. performed cilia and gene expression analyses in human tissue samples. K.B.G. provided assistance with gene expression analysis. E.Z. conduced RNA-seq data processing and analysis. J.L.S. provided technical advice, support and data analysis for electron microscopy studies.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Haotian Zhao.

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https://doi.org/10.1038/ncb3327

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