Wnt/β-catenin信号的激活对于脉络丛的肿瘤发生至关重要

脉络丛（CHP）是位于脑室中的分泌上皮结构。脉络丛肿瘤（CPT）是罕见的肿瘤，主要发生在儿童恶性肿瘤增强的年轻患者中。对肿瘤病理学的了解不足和有效模型的可用性有限，CPT治疗受到阻碍。分析了CPT患者的基因组和转录组数据以识别假定的病理途径。使用细胞和分子技术来验证CPT患者样品中的生物信息学结果。在CPT细胞中评估了Wnt/β-catenin信号传导的药理抑制。在CRISPR-Cas9衍生的敲除和Wnt/β-catenin途径基因的过表达后，进行了基于细胞的CHP细胞系测定。通过APC的CRISPR-CAS9衍生的敲除生成3D CPT模型。我们发现Wnt/β-catenin信号在人CPT中激活，这可能是由于CPT基因组的大规模染色体不稳定性事件。我们证明了CPT衍生的细胞依赖于自分泌Wnt/β-catenin信号传导以生存。组成型Wnt/β-catenin途径通过敲除负调节剂APC或配体Wnt3a的过表达，在CHP 2D体外模型中诱导了肿瘤性特性。通过用有效的GSK3β抑制剂处理，CHP器官中Wnt/β-catenin途径的激活增加，减少了成熟的CHP上皮细胞的分化。值得注意的是，APC的耗竭足以诱导CHP类器官的致癌转化。版权所有。有关商业重复使用，请联系reprints@oup.com，以获取转载和翻译权以进行转载。所有其他权限都可以通过我们的restrimlink服务通过我们网站上文章页面上的“权限链接”获得 - 有关更多信息，请联系journals.permissions.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.