侵袭性高级别 NF2 突变脑膜瘤通过上调 VGLL4 和 FAT3/4 下调致癌 YAP 信号。

IF 3.7 Q1 CLINICAL NEUROLOGY
Neuro-oncology advances Pub Date : 2024-08-24 eCollection Date: 2024-01-01 DOI:10.1093/noajnl/vdae148
Abigail G Parrish, Sonali Arora, H Nayanga Thirimanne, Dmytro Rudoy, Sebastian Schmid, Philipp Sievers, Felix Sahm, Eric C Holland, Frank Szulzewsky
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引用次数: 0

摘要

背景:脑膜瘤是成人最常见的原发性中枢神经系统肿瘤:脑膜瘤是成人最常见的原发性中枢神经系统肿瘤。虽然脑膜瘤通常是良性的,但也有一部分级别较高,最终会致命。大约一半的脑膜瘤含有 NF2 失活突变,导致致癌 YAP1 活性失调。良性 NF2 突变脑膜瘤除了 NF2 失活外,几乎没有其他基因事件,而侵袭性高级别 NF2 突变脑膜瘤则经常携带高度异常的基因组。目前还不清楚不同级别的NF2突变脑膜瘤是否同样依赖YAP活性:我们分析了一大批人类脑膜瘤的大量和单细胞RNA-Seq数据,以检测YAP1靶基因和Hippo效应因子的表达以及体外细胞系实验:结果:与良性脑膜瘤相比,侵袭性NF2突变脑膜瘤的YAP1靶基因表达水平降低,YAP1拮抗剂VGLL4和上游调节因子FAT3/4的表达水平升高。YAP1靶基因的表达减少以及VGLL4和FAT3/4的高表达与复发风险的增加密切相关。在体外,VGLL4的过表达导致良性NF2突变型脑膜瘤细胞中YAP活性的下调,证实了在侵袭性NF2突变型脑膜瘤中观察到的VGLL4表达与YAP活性水平下降之间的直接联系:我们的研究结果为良性和侵袭性 NF2 突变脑膜瘤的生物学特性提供了新的视角,并可能对针对 NF2 突变脑膜瘤中致癌 YAP1 活性的疗法的疗效产生重要影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.

Background: Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half of all meningiomas harbor inactivating mutations in NF2, leading to deregulation of oncogenic YAP1 activity. While benign NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. It is unclear if NF2 mutant meningiomas of different grades are equally reliant on YAP activity.

Methods: We analyzed bulk and single-cell RNA-Seq data from a large cohort of human meningiomas for the expression of YAP1 target genes and Hippo effectors as well as in vitro cell line experiments.

Results: Aggressive NF2 mutant meningiomas harbor decreased expression levels of YAP1 target genes and increased expression levels of the YAP1 antagonist VGLL4 and the upstream regulators FAT3/4 compared to their benign counterparts. Decreased expression of YAP1 target genes as well as high expression of VGLL4 and FAT3/4 is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas.

Conclusions: Our results shed new insight into the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

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CiteScore
6.20
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