Abstract

Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

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Acknowledgements

We thank T. Kobayashi (Harvard University, Boston, USA) for providing the LIN28A(3x)-IRES-eGFP plasmid, D. Rowitch (University of Cambridge, Cambridge, USA) for providing MSCV-IRES-GFP and MSCV-Cre-IRES-GFP plasmids, and D. Baltimore (Pasadena, CA, USA) for providing the Lin28A-IRES-GFP plasmid. We thank R. Toftgård, (Karolinska Institute, Stockholm, Sweden), for providing Sufu−/− MEFs, J. Chen (Stanford University School of Medicine, Stanford, USA) for providing Smo−/− MEFs, and R. Lipinski (University of Wisconsin, Madison, USA) for providing Gli1−/−, Gli2−/−, and Gli3−/− MEFs. We thank H. Blum and S. Krebs for assistance with murine gene-expression data (Gene Center Munich, Germany). We thank S. Occhionero, M. Burmester, M. Wagner, and M. Schmidt (LMU, Munich, Germany) and M. Gregersen and I. Nachtigall (UKE Hamburg, Germany) for excellent technical support, and P. Bonert, P. Liebmann, C. Mann, and M. Wellisch (LMU, Munich, Germany) for animal husbandry. We thank K. Hartmann from the mouse pathology core facility (UKE Hamburg, Germany) for processing immunohistochemical stainings. We are indebted to all members of the Schüller group for very fruitful discussions. This work was supported by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg and grants from the Deutsche Krebshilfe (Max-Eder junior research program to U.S.), the Wilhelm Sander Foundation (to U.S.), the Else-Kröner-Fresenius Foundation (to U.S. and J.E.N.), the K.L. Weigand foundation (to J.E.N.) and the Association “Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München e.V.” (to J.E.N.).

Author information

Author notes

    • Daniel J Merk

    Present address: Cancer Biology and Pediatric Oncology, Dana–Farber Cancer Institute, Boston, Massachusetts, USA.

    • Julia E Neumann
    •  & Annika K Wefers

    These authors contributed equally to this work.

Affiliations

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

    • Julia E Neumann
    • , Annika K Wefers
    • , Edoardo Bianchi
    • , Marie Bockstaller
    • , Mario M Dorostkar
    • , Valerie Meister
    • , Pia Schindler
    • , Daniel J Merk
    • , Mehdi Shakarami
    •  & Ulrich Schüller
  2. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Julia E Neumann
    •  & Ulrich Schüller
  3. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.

    • Julia E Neumann
    • , Pia Schindler
    •  & Ulrich Schüller
  4. Department of Neuropathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

    • Annika K Wefers
    •  & Andrey Korshunov
  5. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Annika K Wefers
    •  & Andrey Korshunov
  6. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.

    • Annika K Wefers
    •  & Andrey Korshunov
  7. Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Sander Lambo
    • , Tanvi Sharma
    • , Lukas Chavez
    •  & Marcel Kool
  8. German Center for Neurodegenerative Diseases, Munich, Germany.

    • Mario M Dorostkar
  9. HIT-MED Study Center, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Katja von Hoff
  10. Reference Center for Neuroradiology, University Hospital of Würzburg, Würzburg, Germany.

    • Johannes Nowak
    •  & Monika Warmuth-Metz
  11. Department of Diagnostic and Interventional Radiology, University Hospital of Würzburg, Würzburg, Germany.

    • Johannes Nowak
  12. Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University, Munich, Germany.

    • Marlon R Schneider
    •  & Ingrid Renner-Müller
  13. Walter Brendel Center, Ludwig-Maximilians-University, Munich, Germany.

    • Mehdi Shakarami
  14. Neurosurgical Research, Ludwig-Maximilians-University, Munich, Germany.

    • Rainer Glass
  15. Department of Pathology & Laboratory Medicine, University of Calgary, Canada.

    • Jennifer A Chan
  16. Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • M Mark Taketo
  17. Department of Informatics, University of Hamburg, Hamburg, Germany.

    • Philipp Neumann
  18. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Ulrich Schüller

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Contributions

J.E.N., A.K.W., and U.S. conceived the project and wrote the manuscript. J.E.N and A.K.W. conducted the majority of experiments. E.B., M.B., V.M., P.S., and M.S. performed experiments. J.N., P.N., L.C., T.S., and M.M.D. performed computational analysis on large-scale data; R.G., M.M.T., J.A.C., M.R.S., I.R-M., and D.J.M. provided assistance with mouse experiments and cell lines. S.L., A.K., and M.K. generated the sequencing data. M.K. generated human miRNA-seq data. K.v.H., J.N., and M.W.-M. provided assistance with human MRI data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ulrich Schüller.

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https://doi.org/10.1038/nm.4402

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