Artikel
A mouse model for Embryonal Tumors with Multilayered Rosettes (ETMRs) predicts tumor responsiveness to Sonic hedgehog inhibitors
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Veröffentlicht: | 25. August 2015 |
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Gliederung
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Introduction: Embryonal Tumors with Multilayered Rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with fatal outcome. These tumors are characterized by an amplification on chromosome 19 (C19MC), high LIN28A expression and an activation of WNT- and Sonic hedgehog (SHH)-target genes.
Objectives: In order to find causal treatment strategies, we aimed to study the relevance of the WNT- and SHH- pathway for the development of ETMRs.
Materials and methods: In order to activate the Wnt- and the Shh- pathway in vivo, we generated hGFAP-cre::Ctnnb1(ex3)Fl/+SmoM2Fl/+ mice, which express a stabilized form of beta-Catenin and a mutant from of Smoothened in a broad range of neural precursor cells. For in vitro treatment analyses, primary hGFAP-cre::Ctnnb1(ex3)Fl/+SmoM2Fl/+ tumor cells, the human ETMR line BT183 and neural Ctnnb1(ex3)Fl/+SmoM2Fl/+ precursor cells, transduced with IRES-GFP, Cre-IRES-GFP and LIN28A-IRES-GFP viruses, were grown in spheres.
Results: We show here that the overexpression of LIN28A, which is a hallmark of human ETMRs, drives Shh and Wnt signaling through the regulation of let7 miRNAs. The simultaneous activation of Shh and Wnt signaling in turn is sufficient to induce ETMRs from neural precursors of the murine cortical subventricular zone (SVZ). These tumors are well responsive to the Shh inhibitor Arsenic trioxide (ATO), and the ATO treatment of immunocompromised mice harboring orthotopically injected human ETMR cells finally demonstrates that inhibition of Shh signaling may serve as a therapeutic option for patients with ETMRs.
Conclusion: We show here that Wnt and Shh signalling are crucially involved in the pathogenesis of ETMRs. Consequently, treatment of ETMRs with Shh inhibitors is effective in mice and should be evaluated for the treatment of future ETMR patients.