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.

中文翻译：

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具有多层玫瑰花结的胚胎肿瘤小鼠模型揭示了Sonic-hedgehog抑制剂的治疗潜力。

具有多层玫瑰花结（ETMR）的胚胎肿瘤最近已被描述为一种罕见的小儿脑肿瘤，具有致命的结局。我们在这里显示ETMRs的特征是Shh和Wnt信号的并行激活。在组织学和整体基因表达分析的基础上，在小鼠神经前体中这些途径的共激活足以在体内诱导类似于人类的ETMR样肿瘤，这表明顶端的放射状胶质细胞可能是肿瘤细胞。起源。LIN28A的过表达是人类ETMR的标志，它通过下调let7-miRNA增强了这些前体细胞中的Sonic-hedgehog（Shh）和Wnt信号，并且在Gli的水平检测到LIN28A / let7a与Shh途径的相互作用。 mRNA。最后，移植到免疫功能低下的宿主小鼠中的人类ETMR细胞对SHH抑制剂三氧化二砷（ATO）有反应。我们的工作提供了一种新型的小鼠模型，用于研究这种肿瘤类型，证明了Wnt和Shh激活在ETMRs生长中的驱动作用，并提出了抑制Shh信号的下游作用，作为ETMRs患者的治疗选择。