The Critical Role of Wnt/β-catenin Signaling in Choroid Plexus Tumorigenesis

Background Introduction

The choroid plexus (CHP) is a secretory epithelial structure located in the brain ventricles, primarily responsible for the secretion of cerebrospinal fluid (CSF) and the establishment of the blood-CSF barrier. Choroid plexus tumors (CPTs) are rare intracranial tumors that predominantly occur in children, especially in infants under one year of age, accounting for 20% of pediatric tumors. CPTs are classified into choroid plexus papilloma (CPP), atypical choroid plexus papilloma (ACPP), and choroid plexus carcinoma (CPC). While CPP occurs in both children and adults with a relatively favorable prognosis, CPC is highly aggressive, with a 5-year survival rate of only 26%-73%. Currently, the treatment of CPT primarily relies on surgical resection, but due to insufficient understanding of the tumor’s pathological mechanisms and the lack of specific chemotherapeutic drugs, treatment outcomes are limited.

In recent years, genomic and transcriptomic studies have revealed extensive chromosomal instability in CPTs, but the specific driver gene mutations remain unclear. The Wnt/β-catenin signaling pathway plays a significant role in various cancers, particularly in epithelial tumors. However, the role of the Wnt/β-catenin signaling pathway in CPT has not been thoroughly investigated. Therefore, this study aims to explore the critical role of the Wnt/β-catenin signaling pathway in CPT tumorigenesis and establish the first 3D in vitro model to support future pathological and therapeutic research.

Source of the Paper

This paper was co-authored by Kim Hoa Ho, Marleen Trapp, Catello Guida, and others, with the research team coming from multiple institutions, including the German Cancer Research Center (DKFZ), Heidelberg University, and the Medical Faculty Mannheim of Heidelberg University. The paper was published online in advance on August 31, 2024, in the journal Neuro-Oncology, with the DOI 10.1093/neuonc/noae176.

Research Process and Results

1. Genomic and Transcriptomic Data Analysis

The research team first analyzed genomic and transcriptomic data from CPT patients to identify potential pathological pathways. By analyzing a published gene expression microarray dataset (GSE14098), they found that the Wnt/β-catenin signaling pathway was significantly activated in CPP. Further whole-genome sequencing (WGS) data revealed extensive structural variants (SVs) and single nucleotide variants (SNVs) in CPTs, which affected multiple genes in the Wnt/β-catenin signaling pathway, including APC, Wnt2b, and Fzd2.

2. Cellular and Molecular Experimental Validation

To validate the bioinformatics analysis results, the research team conducted cellular and molecular experiments on CPT patient samples. Using CRISPR-Cas9 technology to knock out the APC gene or overexpress the Wnt3a ligand, the researchers found that activation of the Wnt/β-catenin signaling pathway significantly enhanced the tumorigenic properties of choroid plexus cells, including anchorage-independent growth and brain parenchyma invasion. Additionally, treatment of the CPP cell line HIBCCP with the Wnt inhibitor Wnt974 significantly inhibited cell proliferation and survival, further demonstrating the dependence of CPT cells on the Wnt/β-catenin signaling pathway.

3. Establishment of a 3D Choroid Plexus Organoid Model

To more accurately simulate the pathological process of CPT, the research team generated choroid plexus organoids (CHP organoids) using human induced pluripotent stem cells (hiPSCs). By knocking out the APC gene using CRISPR-Cas9 technology, the researchers successfully induced tumor formation in the choroid plexus organoids. These tumor organoids exhibited pathological features similar to human CPTs, including increased cell proliferation and reduced expression of differentiation markers. Furthermore, methylation analysis showed that APC-knockout organoids closely resembled the molecular characteristics of high-risk pediatric CPTs.

Research Conclusions

This study is the first to reveal the critical role of the Wnt/β-catenin signaling pathway in CPT tumorigenesis. Through genomic and transcriptomic analysis, cellular experiments, and the establishment of a 3D organoid model, the research team demonstrated that activation of the Wnt/β-catenin signaling pathway is a key driver of CPT development. This discovery not only provides new insights into the pathological mechanisms of CPT but also offers a reliable in vitro model for future therapeutic research.

Research Highlights

1. Activation of the Wnt/β-catenin Signaling Pathway: This study systematically demonstrated for the first time the activation of the Wnt/β-catenin signaling pathway in CPT and revealed its mechanism driven by chromosomal instability events.
2. Establishment of a 3D Organoid Model: The research team successfully established the first 3D organoid model for CPT, providing an important tool for future pathological and drug screening research.
3. Potential Application of Wnt Inhibitors: Through experiments with the Wnt inhibitor Wnt974, the research team demonstrated the potential of targeting the Wnt/β-catenin signaling pathway in CPT treatment.

Research Significance

This study not only provides new insights into the pathological mechanisms of CPT but also offers a reliable in vitro model for future therapeutic research. By revealing the critical role of the Wnt/β-catenin signaling pathway in CPT, the research team has laid the foundation for the development of new targeted therapeutic strategies. Additionally, the establishment of the 3D organoid model will greatly advance basic research and drug development for this rare but deadly pediatric tumor, bringing new hope for its treatment.