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 fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh- and Wnt-signaling. Co-activation of these pathways in murine neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts based on histology and global gene expression analyses, and 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 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 findings provide a novel mouse model to study this tumor type, demonstrate the driving role of Wnt- and Shh-activation in the growth of ETMRs and propose downstream inhibition of Shh-signaling as a therapeutic option for patients with ETMRs.

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Neumann JE, Wefers AK, Lambo S, Bianchi E, Bockstaller M, Dorostkar MM, Meister V, Schindler P, Korshunov A, von Hoff K, Nowak J, Warmuth-Metz M, Schneider MR, Renner-Müller I, Merk DJ, Shakarami M, Sharma T, Chavez L, Glass R, Chan JA, Taketo MM, Neumann P, Kool M, Schüller U