Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Nat Med. 2017 Oct;23(10):1191-1202. doi: 10.1038/nm.4402. Epub 2017 Sep 11.
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.
胚胎性肿瘤伴多层菊形团（ETMRs）最近被描述为一种具有致命结局的罕见儿科脑肿瘤的新实体。我们在这里表明，ETMRs 的特征是 Shh 和 Wnt 信号的平行激活。在小鼠神经前体细胞中共同激活这些途径足以在体内诱导出类似于人类 ETMR 的肿瘤，这些肿瘤在组织学和全基因表达分析上与人类 ETMR 相似，并指出顶侧放射状神经胶质细胞可能是肿瘤的起源细胞。LIN28A 的过表达是人类 ETMR 的标志，通过下调 let7-miRNA，在这些前体细胞中增强 Sonic-hedgehog (Shh) 和 Wnt 信号，并且在 Gli mRNA 水平检测到 LIN28A/let7a 与 Shh 途径的相互作用。最后，移植到免疫缺陷宿主小鼠中的人 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的小鼠模型，可用于研究这种肿瘤类型，证明了 Wnt 和 Shh 激活在 ETMR 生长中的驱动作用，并提出了抑制 Shh 信号作为 ETMR 患者治疗选择的可能性。
