WNT and SHH Drive the Tumorigenesis of a Rare Embryonal Brain Tumor

Embryonal tumors with multilayered rosettes (ETMR) are highly malignant rare pediatric brain tumors that harbor a focal amplification at chromosome 19q13.42 and exhibit overexpression of LIN28A, which inhibits the maturation of let-7 miRNA; further, a subset of ETMRs exhibit upregulation of WNT and SHH target genes. To elucidate the roles of WNT and SHH activation in ETMR, Neumann and colleagues examined two patient cohorts and generated a transgenic murine model of ETMR. ETMRs exhibited enrichment of WNT and SHH signaling and harbored mutations in WNT and SHH pathway genes such as CTNNB1. Targeted activation of WNT (GB), SHH (GS), or both WNT and SHH (GBS) in neural precursor cells showed that coactivation of WNT and SHH in GBS mice promoted the formation of tumors which histologically resembled human ETMR. SOX2⁺/PAX6⁺ apical radial glia of the cortical ventricular zone (VZ) were identified as the candidate cell of origin for GBS tumors and human ETMRs, and GBS tumors and human ETMRs exhibited similar gene expression patterns. LIN28A was absent in GBS tumors, suggesting that LIN28A may drive the simultaneous activation of WNT and SHH signaling. Lin28A overexpression in mouse neurospheres induced increased neurosphere growth and upregulation of WNT and SHH target genes; conversely, LIN28A ablation in human ETMR cells drove decreased proliferation and the downregulation of WNT and SHH target genes. Treatment of Lin28A-overexpressing neurospheres with a let-7a mimic resulted in the downregulation of GLI2, and expression of let-7a miRNA in mouse embryonic fibroblasts or human ETMR cells resulted in increased Gli1/2/3 levels. Treatment with a GLI2 inhibitor inhibited ETMR growth in vitro and in vivo. These results describe a mouse model of ETMR driven by concomitant WNT and SHH activation that recapitulates the human disease, provide insight into the role of WNT and SHH in ETMR tumorigenesis, and identify a potential therapeutic strategy for patients with ETMR.

Neumann JE, Wefers AK, Lambo S, Bianchi E, Bockstaller M, Dorostkar MM, et al. A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of sonic-hedgehog inhibitors. Nature Medicine 2017 Sep 11 [Epub ahead of print].

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