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

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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FROM A _DE NOVO_ MURINE BRAIN CANCER MODEL Article 07 January 2021 CELLULAR HIERARCHIES OF EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR–LIGAND

INTERACTIONS Article Open access 26 May 2025 MOUSE MODELS OF PEDIATRIC HIGH-GRADE GLIOMAS WITH MYCN AMPLIFICATION REVEAL INTRATUMORAL HETEROGENEITY AND LINEAGE SIGNATURES Article Open access

24 November 2023 ACCESSION CODES PRIMARY ACCESSIONS GENE EXPRESSION OMNIBUS * GSE103348 * GSE14295 * GSE21858 * GSE34824 * GSE36245 * GSE37418 * GSE64415 * GSE65000 * GSE73038 REFERENCES *

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(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 and Annika K Wefers: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS

* 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 * Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Julia E Neumann & Ulrich

Schüller * Research Institute Children's Cancer Center Hamburg, Hamburg, Germany Julia E Neumann, Pia Schindler & Ulrich Schüller * Department of Neuropathology,

Ruprecht-Karls-University Heidelberg, Heidelberg, Germany Annika K Wefers & Andrey Korshunov * Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg,

Germany Annika K Wefers & Andrey Korshunov * German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany Annika K Wefers & Andrey Korshunov * Division of Pediatric

Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Sander Lambo, Tanvi Sharma, Lukas Chavez & Marcel Kool * German Center for Neurodegenerative Diseases, Munich,

Germany Mario M Dorostkar * Department of Pediatric Hematology and Oncology, HIT-MED Study Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Katja von Hoff * Reference

Center for Neuroradiology, University Hospital of Würzburg, Würzburg, Germany Johannes Nowak & Monika Warmuth-Metz * Department of Diagnostic and Interventional Radiology, University

Hospital of Würzburg, Würzburg, Germany Johannes Nowak * Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University, Munich, Germany Marlon R Schneider & 

Ingrid Renner-Müller * Walter Brendel Center, Ludwig-Maximilians-University, Munich, Germany Mehdi Shakarami * Neurosurgical Research, Ludwig-Maximilians-University, Munich, Germany Rainer

Glass * Department of Pathology & Laboratory Medicine, University of Calgary, Canada Jennifer A Chan * Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto

University, Kyoto, Japan M Mark Taketo * Department of Informatics, University of Hamburg, Hamburg, Germany Philipp Neumann * Department of Pediatric Hematology and Oncology, University

Medical Center Hamburg-Eppendorf, Hamburg, Germany Ulrich Schüller Authors * Julia E Neumann View author publications You can also search for this author inPubMed Google Scholar * Annika K

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search for this author inPubMed Google Scholar * Tanvi Sharma View author publications You can also search for this author inPubMed Google Scholar * Lukas Chavez View author publications You

can also search for this author inPubMed Google Scholar * Rainer Glass View author publications You can also search for this author inPubMed Google Scholar * Jennifer A Chan View author

publications You can also search for this author inPubMed Google Scholar * M Mark Taketo View author publications You can also search for this author inPubMed Google Scholar * Philipp

Neumann View author publications You can also search for this author inPubMed Google Scholar * Marcel Kool View author publications You can also search for this author inPubMed Google

Scholar * Ulrich Schüller View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–12 and Supplementary Table 1 (PDF 15663 kb)

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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 Download citation * Received: 07 June 2016 * Accepted: 15 August 2017 * Published: 11 September 2017 * Issue Date: 01 October 2017 * DOI:

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