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


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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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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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.

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Correspondence to Ulrich Schüller.

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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).

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