BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
- Klíčová slova
- APC, Wnt signaling, brain tumor, choroid plexus organoid, rare childhood cancer,
- MeSH
- beta-katenin * metabolismus genetika MeSH
- karcinogeneze * metabolismus patologie MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- nádory plexus chorioideus * patologie metabolismus genetika MeSH
- proliferace buněk MeSH
- regulace genové exprese u nádorů MeSH
- signální dráha Wnt * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- beta-katenin * MeSH
We present five families of paediatric patients suffering from choroid plexus carcinoma in which we found germline TP53 mutations. Only one of the families conformed to the criteria of Li-Fraumeni syndrome and only three (including the Li-Fraumeni syndrome family) met the Chompret criteria for germline TP53 mutation testing. In the remaining two families no family history of cancer was identified and/or the parents of the patient were shown not to carry the mutation. Our results give further support to the notion that the occurrence of this rare paediatric tumour, especially in combination with a positive family history of cancer, but possibly also without any family history, may be an indicator of a germline TP53 mutation. The identification of this genetic defect has important consequences for cancer prevention and treatment in affected families.
- MeSH
- dítě MeSH
- dospělí MeSH
- geny p53 genetika MeSH
- lidé MeSH
- missense mutace genetika MeSH
- mladiství MeSH
- nádory plexus chorioideus genetika MeSH
- rodokmen MeSH
- sekvence aminokyselin genetika MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH