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.

中文翻译：

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原始脑膜层对产前Smo激活的颅底脑膜内皮脑膜瘤形成的选择性脆弱性。

平滑肌（SMO）的体细胞激活突变是胚胎声波刺猬（SHH）信号传导途径的组成部分，在3-5％的I级脑膜瘤中被发现，其中大多数对应于位于前颅底的脑膜瘤性脑膜瘤。通过在小鼠中产生不同的发育阶段特异性条件活化，我们定义了一个受限的发育窗口，在此期间，前列腺素D2-合酶阳性的中胚层衍生的脑膜脑膜层中Smo的条件活化导致脑膜内皮脑膜瘤的形成。我们显示从颅骨基地蛛网膜激活Smo激活以启动肿瘤发展的选择性脆弱。这种产前时期和特定的地形与SHH信号传导参与颅面和脑膜图案形成的时机和位置有关，强烈证实了Smo激活的脑膜瘤的起源起源的假说。最后，我们提供了SMO抑制剂Sonidegib的临床前体外证据，支持了难治性SMO突变型脑膜瘤靶向治疗的进一步临床前和临床评估。