Wnt/β-链蛋白信号通路的激活对脉络丛肿瘤发生的关键作用

脉络丛（ChP）是位于脑室中的分泌上皮结构。脉络丛肿瘤（CPTs）为少见的新生物，主要发生在年轻患者中，儿童中恶性程度更高。由于对肿瘤病理机制认识不足及有效模型有限，CPT的治疗受到制约。通过分析CPT患者的基因组和转录组数据，旨在识别潜在的致病途径。采用细胞和分子技术验证生物信息学分析结果在CPT患者样本中的正确性。评估Wnt/β-链蛋白信号通路抑制剂的药理作用。对CRISPR-Cas9敲除和过表达Wnt/β-链蛋白通路相关基因的脉络丛细胞系进行细胞实验。利用CRISPR-Cas9敲除APC构建了三维CPT模型。研究发现Wnt/β-链蛋白信号在人类CPT中被激活，可能由CPT基因组的大片段染色体不稳定事件引起。证实CPT来源的细胞依赖自分泌的Wnt/β-链蛋白信号生存。通过敲除阴性调节因子APC或过表达配体WNT3A，导致Wnt/β-链蛋白通路持续激活，从而在ChP二维体外模型中引发肿瘤特性。利用强效GSK3β抑制剂刺激的ChP类器官中，Wnt/β-链蛋白通路的激活增强了成熟ChP上皮细胞的分化。值得注意的是，APC的缺失足以诱导ChP类器官的肿瘤转化。本研究确认Wnt/β-链蛋白信号是CPT肿瘤发生的关键驱动因素，并首次建立了用于未来CPT病理和治疗研究的三维体外模型。© 作者（们）2024年发表。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业再利用，请联系reprints@oup.com获取再版和翻译权。其他权限可通过我们网站上的Permissions链接，使用RightsLink服务获得。详情请联系journals.permissions@oup.com。

The choroid plexus (ChP) is the secretory epithelial structure located in the brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of tumor pathology and the limited availability of valid models.Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and overexpression of Wnt/β-catenin pathway genes. A 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC.We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knockout of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of the Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelial cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids.Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.