基于人类胚胎干细胞的模型揭示了 FOXR2 激活的中枢神经系统神经母细胞瘤的起源细胞。

IF 3.7 Q1 CLINICAL NEUROLOGY Neuro-oncology advances Pub Date : 2024-08-12 eCollection Date: 2024-01-01 DOI:10.1093/noajnl/vdae144
Hitomi N Royston, Autumn B Hampton, Dhruv Bhagat, Evonne F Pinto, Miriam D Emerson, Kosuke Funato
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引用次数: 0

摘要

背景:FOXR2激活的中枢神经系统(CNS)神经母细胞瘤(CNS NB-FOXR2)是最近发现的一种脑肿瘤亚型,其特点是转录因子FOXR2的高表达,主要是由于基因组重排所致。然而,包括起源细胞类型在内的确切致病机制仍难以确定:方法:对患者肿瘤进行基因表达分析,以确定可能的起源细胞类型。结果:我们的数据显示,中枢神经系统 NB-FOXR2 的形成与胚胎干细胞有关:我们的数据显示,中枢神经系统NB-FOXR2肿瘤表达与内侧神经节突起(MGE)相关的高水平系谱标记基因,内侧神经节突起是位于发育中的腹侧前脑的瞬时结构。我们的模型证实了 FOXR2 对增殖和体内致瘤性的细胞类型特异性影响。此外,我们还发现 FOXR2 过表达会通过抑制内源性 RAS 抑制剂 DIRAS3 激活 MEK/ERK 信号通路。与不表达FOXR2的细胞相比,MEK抑制剂曲美替尼更能抑制表达FOXR2的MGE祖细胞的增殖:我们的研究共同证明,MGE祖细胞是中枢神经系统NB-FOXR2的起源细胞,FOXR2激活了MEK/ERK信号通路,为治疗提供了潜在靶点。
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A human embryonic stem cell-based model reveals the cell of origin of FOXR2-activated CNS neuroblastoma.

Background: FOXR2-activated central nervous system (CNS) neuroblastoma (CNS NB-FOXR2) is a recently identified subtype of brain tumor characterized by the elevated expression of the transcription factor FOXR2 mainly due to genomic rearrangements. However, the precise pathogenic mechanisms, including the cell type of origin, remain elusive.

Methods: A gene expression analysis of patient tumors was performed to identify putative cell types of origin. Based on this prediction, a new human embryonic stem cell-based model was developed to validate the origin and to examine the molecular and cellular mechanisms underlying the formation of CNS NB-FOXR2.

Results: Our data showed that CNS NB-FOXR2 tumors express a high level of lineage marker genes associated with the medial ganglionic eminence (MGE), a transient structure located in the developing ventral forebrain. Our model confirmed the cell-type-specific effect of FOXR2 on the proliferation and in vivo tumorigenicity. Additionally, we found that FOXR2 overexpression activated the MEK/ERK signaling pathway through a suppression of the endogenous RAS inhibitor DIRAS3. The MEK inhibitor trametinib suppressed the proliferation of FOXR2-expressing MGE progenitors more than nonexpressing cells.

Conclusions: Our study collectively demonstrates that MGE progenitors are the cell of origin of CNS NB-FOXR2 and that FOXR2 activates the MEK/ERK signaling pathway, providing a potential therapeutic target.

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