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A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

Nature Medicine volume 23, pages 1191–1202 (2017)Cite this article

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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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Figure 1: Simultaneous activation of the Wnt and Shh pathways in neural precursors leads to the formation of forebrain tumors.
Figure 2: Radial glia cells of the cortical VZ are candidate cells of origin for GBS tumors and human ETMRs.
Figure 3: GBS tumors are similar to human ETMRs.
Figure 4: Wnt and Shh targets lie downstream of LIN28A.
Figure 5: Effects of Lin28A on Wnt and Shh are mediated via let-7a.
Figure 6: GBS tumors and ETMRs respond to arsenic trioxide (ATO).

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References

  1. Li, M. et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 16, 533–546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Spence, T. et al. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol. 128, 291–303 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Korshunov, A. et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol. 120, 253–260 (2010).

    Article  PubMed  Google Scholar 

  4. Korshunov, A. et al. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathol. 124, 875–881 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kleinman, C.L. et al. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat. Genet. 46, 39–44 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Picard, D. et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol. 13, 838–848 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Korshunov, A. et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol. 128, 279–289 (2014).

    Article  PubMed  Google Scholar 

  8. Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zurawel, R.H., Chiappa, S.A., Allen, C. & Raffel, C. Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res. 58, 896–899 (1998).

    CAS  PubMed  Google Scholar 

  10. Koch, A. et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int. J. Cancer 93, 445–449 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Ishizaki, Y. et al. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int. J. Oncol. 24, 1077–1083 (2004).

    CAS  PubMed  Google Scholar 

  12. Northcott, P.A. et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Al-Fageeh, M., Li, Q., Dashwood, W.M., Myzak, M.C. & Dashwood, R.H. Phosphorylation and ubiquitination of oncogenic mutants of beta-catenin containing substitutions at Asp32. Oncogene 23, 4839–4846 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schwalbe, E.C. et al. Rapid diagnosis of medulloblastoma molecular subgroups. Clin. Cancer Res. 17, 1883–1894 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25, 393–405 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Pöschl, J., Grammel, D., Dorostkar, M.M., Kretzschmar, H.A. & Schüller, U. Constitutive activation of β-catenin in neural progenitors results in disrupted proliferation and migration of neurons within the central nervous system. Dev. Biol. 374, 319–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Schüller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grammel, D. et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 123, 601–614 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Pöschl, J. et al. Wnt/β-catenin signaling inhibits the Shh pathway and impairs tumor growth in Shh-dependent medulloblastoma. Acta Neuropathol. 127, 605–607 (2014).

    Article  PubMed  Google Scholar 

  21. Florio, M. & Huttner, W.B. Neural progenitors, neurogenesis and the evolution of the neocortex. Development 141, 2182–2194 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Florio, M. et al. Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science 347, 1465–1470 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Spence, T. et al. A novel C19MC amplified cell line links Lin28/let-7 to mTOR signaling in embryonal tumor with multilayered rosettes. Neuro-oncol. 16, 62–71 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3, 903–911 (2003).

    Article  PubMed  Google Scholar 

  25. Viswanathan, S.R., Daley, G.Q. & Gregory, R.I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Emami, K.H. et al. A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected]. Proc. Natl. Acad. Sci. USA 101, 12682–12687 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dierks, C. GDC-0449—targeting the hedgehog signaling pathway. Recent Results Cancer Res. 184, 235–238 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Beauchamp, E.M. et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J. Clin. Invest. 121, 148–160 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Kim, J., Lee, J.J., Kim, J., Gardner, D. & Beachy, P.A. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc. Natl. Acad. Sci. USA 107, 13432–13437 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chenn, A. & Walsh, C.A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Nowak, J. et al. Systematic comparison of MRI findings in pediatric ependymoblastoma with ependymoma and CNS primitive neuroectodermal tumor not otherwise specified. Neuro-oncol. 17, 1157–1165 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Noctor, S.C., Martínez-Cerdeño, V., Ivic, L. & Kriegstein, A.R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Sato, H. et al. Embryonal tumor with abundant neuropil and true rosettes in the brainstem: case report. J. Neurosurg. Pediatr. 16, 291–295 (2015).

    Article  PubMed  Google Scholar 

  35. Nowak, J. et al. MRI characteristics of ependymoblastoma: results from 22 centrally reviewed cases. AJNR Am. J. Neuroradiol. 35, 1996–2001 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gessi, M. et al. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am. J. Surg. Pathol. 33, 211–217 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yang, M. et al. Lin28 promotes the proliferative capacity of neural progenitor cells in brain development. Development 142, 1616–1627 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bentwich, I. et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat. Genet. 37, 766–770 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Lei, X.X. et al. Determinants of mRNA recognition and translation regulation by Lin28. Nucleic Acids Res. 40, 3574–3584 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Weingart, M.F. et al. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget 6, 3165–3177 (2015).

    Article  PubMed  Google Scholar 

  41. Zeng, Y. et al. Lin28A binds active promoters and recruits Tet1 to regulate gene expression. Mol. Cell 61, 153–160 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Schmidt, C. et al. Pre-clinical drug screen reveals topotecan, actinomycin D and volasertib as potential new therapeutic candidates for ETMR brain tumor patients. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/nox093 (2017).

  43. Iland, H.J. et al. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2, e357–e366 (2015).

    Article  PubMed  Google Scholar 

  44. Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Pajtler, K.W. et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27, 728–743 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Arnold, K. et al. Sox2+ adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317–329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shultz, L.D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J. 18, 5931–5942 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Papaioannou, G., Inloes, J.B., Nakamura, Y., Paltrinieri, E. & Kobayashi, T. let-7 and miR-140 microRNAs coordinately regulate skeletal development. Proc. Natl. Acad. Sci. USA 110, E3291–E3300 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hovestadt, V. et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 125, 913–916 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nowak, J. et al. Ependymoblastoma of the brainstem: MRI findings and differential diagnosis. Pediatr. Blood Cancer 61, 1132–1134 (2014).

    Article  PubMed  Google Scholar 

  53. Friedrich, C. et al. Primitive neuroectodermal tumors of the brainstem in children treated according to the HIT trials: clinical findings of a rare disease. J. Neurosurg. Pediatr. 15, 227–235 (2015).

    Article  PubMed  Google Scholar 

  54. Stock, K. et al. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat. Med. 18, 1232–1238 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Svärd, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Sinha, S. & Chen, J.K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol. 2, 29–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Lipinski, R.J., Bijlsma, M.F., Gipp, J.J., Podhaizer, D.J. & Bushman, W. Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines. BMC Cell Biol. 9, 49 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kingston, R.E., Chen, C.A. & Okayama, H. Calcium phosphate transfection. Curr. Protoc. Cell Biol. Chapter 20, Unit 20.23 (2003).

  59. Wani, S. & Cloonan, N. Profiling direct mRNA-microRNA interactions using synthetic biotinylated microRNA-duplexes. Preprint at https://doi.org/10.1101/005439 (2014).

  60. Schüller, U. et al. Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol. Cell. Biol. 27, 8259–8270 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pöschl, J. et al. Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans. Oncogene 30, 4721–4730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Jones, D.T. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sahm, F. et al. Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol. 131, 903–910 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Yang, H. & Wang, K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat. Protoc. 10, 1556–1566 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lambert, N. et al. Genes expressed in specific areas of the human fetal cerebral cortex display distinct patterns of evolution. PLoS One 6, e17753 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pöschl, J. et al. Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts. Acta Neuropathol. 128, 123–136 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kanehisa, M. & Goto, S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.).

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Author notes

  1. Daniel J Merk

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

  2. Julia E Neumann and Annika K Wefers: These authors contributed equally to this work.

Authors and 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. Department of Pediatric Hematology and Oncology, HIT-MED Study Center, 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.

Corresponding author

Correspondence to Ulrich Schüller.

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The authors declare no competing financial interests.

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Neumann, J., Wefers, A., Lambo, S. et al. A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors. Nat Med 23, 1191–1202 (2017). https://doi.org/10.1038/nm.4402

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