Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation
Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation
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DOI：
10.1038/s41388-018-0328-7
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发表时间：
2018-09-06
期刊：
影响因子：
8
通讯作者：
Kalamarides, Michel
中科院分区：
文献类型：
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作者：
Boetto, Julien;Apra, Caroline;Kalamarides, Michel
Smoothened（SMO）的体细胞激活突变是胚胎音刺猬（SHH）信号通路的一个组成部分，在3-5%的I级脑膜瘤中发现，其中大多数对应于位于前颅底的脑膜瘤。通过在小鼠中产生不同发育阶段特异性条件激活，我们定义了一个限制性发育窗口，在此期间，在颅底的前列腺素D2-脱氢酶阳性中胚层来源的脑膜层中Smo的条件激活导致脑膜瘤形成。我们显示了从颅底到Smo激活的蛛网膜的选择性脆弱性，以启动肿瘤的发展。这种产前时期和特定的地形与SHH信号参与颅面和脑膜图案形成的时间和位置相关，强烈证实了Smo激活脑膜瘤发育起源的假设。最后，我们提供了SMO抑制剂Sonidegib疗效的临床前体外证据，支持对难治性SMO突变型脑膜瘤靶向治疗的进一步临床前和临床评价。
Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3-5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation. We show a selective vulnerability of the arachnoid from the skull base to Smo activation to initiate tumor development. This prenatal period and specific topography are correlated to the timing and location of SHH signaling involvement in the formation of craniofacial and meninges patterning, strongly corroborating the hypothesis of a developmental origin for Smo-activated meningiomas. Finally, we provide preclinical in vitro evidence of the efficacy of the SMO-inhibitor Sonidegib, supporting further preclinical and clinical evaluation of targeted treatment for refractory SMO-mutant meningiomas.