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Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas

Oncogene volume 29, pages 1845–1856 (2010)Cite this article

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Abstract

Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.

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Acknowledgements

We thank Rob Wechsler-Reya and James Briscoe for the gift of ptc+/− medulloblastoma pellets and Sox9 antibody respectively. We thank Gary Warnes for expert assistance with the flow cytometry analysis. This work was supported by grants of St Bartholomew's Charitable Foundation, Cancer Research UK, Ali's Dream and Charlie's Challenge Charities to SM and by personal fellowships of Janggen-Pöhn Foundation and Swiss National Science Foundation to RS.

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  1. F L Heppner

    Present address: 7Present address: Department of Neuropathology, Charité—Universitätsmedizin Berlin, Berlin, Germany.,

Authors and Affiliations

  1. Neuroscience Centre, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    R Sutter, O Shakhova, H Bhagat, H Behesti, S Penkar & S Marino

  2. Department of Pathology, Institute of Surgical Pathology, University Hospital, Zürich, Switzerland

    C Sutter, A Santuccione, H Moch & P Schraml

  3. Department of Neurosurgery, University Hospital, Zürich, Switzerland

    R Bernays

  4. Department of Pathology, Institute of Neuropathology, University Hospital, Zürich, Switzerland

    F L Heppner

  5. Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany

    U Schüller

  6. Department of Oncology, University Children's Hospital of Zurich, Zürich, Switzerland

    M Grotzer

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Correspondence to S Marino.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Sutter, R., Shakhova, O., Bhagat, H. et al. Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene 29, 1845–1856 (2010). https://doi.org/10.1038/onc.2009.472

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