Meningioma cells express primary cilia but do not transduce ciliary Hedgehog signals
Meningioma cells express primary cilia but do not transduce ciliary Hedgehog signals
复制标题
DOI：
10.1186/s40478-020-00994-7
复制
发表时间：
2020-07-20
影响因子：
7.1
通讯作者：
Raleigh, David R.
中科院分区：
文献类型：
--
作者：
Findakly, Sarah;Choudhury, Abrar;Raleigh, David R.
脑膜瘤是最常见的原发性颅内肿瘤，但由于对肿瘤生物学的不完全理解，脑膜瘤患者的治疗选择有限。一小部分脑膜瘤在Hedgehog通路中具有体细胞变异，Hedgehog通路是一种保守的基因表达程序，对发育和成体干细胞稳态至关重要。Hedgehog信号通过初级纤毛转导，并且已知Hedgehog通路的误激活是癌症的基础。然而，脑膜瘤中Hedgehog信号传导的机制尚不清楚。在这里，我们使用包含154个人脑膜瘤样本的组织微阵列，NanoString转录谱，原发性脑膜瘤细胞，药理学和CRISPR干扰来研究脑膜瘤中纤毛Hedgehog信号传导的机制。我们的研究结果表明，所有级别的脑膜瘤都可以表达原发性纤毛，但纤毛在间变性肿瘤中不太常见。此外，我们发现在其他情况下致癌的Smoothened等位基因的表达不能激活刺猬转录程序或促进原发性脑膜瘤细胞的增殖。这些数据表明，脑膜瘤可以表达典型的Hedgehog信号所必需的亚细胞结构，但表明它们不表达纤毛Hedgehog信号。
Meningiomas are the most common primary intracranial tumors, but treatment options for meningioma patients are limited due to incomplete understanding of tumor biology. A small percentage of meningiomas harbor somatic variants in the Hedgehog pathway, a conserved gene expression program that is essential for development and adult stem cell homeostasis. Hedgehog signals are transduced through primary cilia, and misactivation of the Hedgehog pathway is known to underlie cancer. Nevertheless, the mechanisms of Hedgehog signaling in meningioma are unknown. Here, we investigate mechanisms of ciliary Hedgehog signaling in meningioma using tissue microarrays containing 154 human meningioma samples, NanoString transcriptional profiling, primary meningioma cells, pharmacology, and CRISPR interference. Our results reveal that meningiomas of all grades can express primary cilia, but that cilia are less prevalent among anaplastic tumors. Moreover, we find that expression of Smoothened alleles that are oncogenic in other contexts fail to activate the Hedgehog transcriptional program or promote proliferation in primary meningioma cells. These data reveal that meningiomas can express the subcellular structure necessary for canonical Hedgehog signaling, but suggest that they do not transduce ciliary Hedgehog signals.