Integrated single-nucleus and spatial transcriptomics define tumour cell metaprograms and tumour microenvironment organisation in choroid plexus tumours
4 affiliations
- 1Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Münster, Germany
- 2Institute of Medical Informatics, University of Münster, Münster, Germany
- 3Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- 4Institute of Neuropathology, University Hospital Münster, Münster, Germany
Abstract
Background: Choroid plexus tumours (CPTs) are rare intraventricular brain neoplasms derived from choroid plexus epithelium, predominantly affecting young children. They include benign choroid plexus papilloma (CPP), atypical CPP (aCPP), and malignant choroid plexus carcinoma (CPC) and segregate into three DNA-methylation subgroups: paediatric A (pedA), paediatric B (pedB), and adult.
Methods: To resolve subtype-specific biology, we performed single-nucleus RNA sequencing on 43 CPTs and integrated 12 non-neoplastic foetal, paediatric, and adult choroid plexus references, complemented by spatial transcriptomics in a subset of 16 tumour sections and 2 normal choroid plexus samples.
Results: Tumour embeddings and correlation analyses demonstrated that CPTs cluster by methylation subtype rather than WHO grade, revealing epigenetically driven relationships despite divergent histology. We identified 10 tumour metaprograms spanning epithelial differentiation, ciliogenesis, proliferation, extra cellular matrix remodelling, and stress responses. PedA and adult tumours showed relatively homogeneous program distribution dominated by differentiation or ciliation states, whereas pedB tumours exhibited marked heterogeneity with selective enrichment of hypoxia, interferon signalling, early stress response, and TGF-β signalling. Spatial mapping revealed consistent anticorrelation of these programs with ciliogenesis and differentiation programs, suggesting stress-associated dedifferentiation. Elevated stress and hypoxia scores correlated with poorer survival. PedB tumours showed enrichment of interferon- and lipid-associated myeloid populations, that carried pro-angiogenic signatures. They were spatially co-localised with hypoxic and interferon I expressing tumour areas, that were predicted to interact with myeloid cells via immunosuppressive cues, shaping a pro-angiogenic, pro-tumour environment.
Conclusions: This study identifies stress- and hypoxia-associated dedifferentiation programs that are selectively enriched in pedB tumours, correlate with poor clinical outcome, and antagonise multiciliogenesis and epithelial differentiation. Their spatial co-localisation with immunosuppressive, pro-angiogenic macrophage populations links developmental arrest to microenvironmental remodelling and aggressive behaviour. These findings provide a biologically grounded framework for risk stratification and highlight hypoxia, angiogenesis and macrophage polarisation as candidate therapeutic targets in high-risk CPTs.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13073-026-01814-8.
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BibTeX
@article{klotergens2026integrated,
title = {{Integrated single-nucleus and spatial transcriptomics define tumour cell metaprograms and tumour microenvironment organisation in choroid plexus tumours}},
author = {Anna Klötergens and Clara Inserte and Flavia W. de Faria and Archana Verma and Erik Schüftan and Rajanya Roy and Victor Banerjee and Thomas K. Albert and I-Na Lu and Uwe Kordes and Denise Obrecht-Sturm and Christian Thomas and Kornelius Kerl},
journal = {Genome Medicine},
year = {2026},
month = nov,
doi = {10.1186/s13073-026-01814-8},
url = {https://doi.org/10.1186/s13073-026-01814-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated single-nucleus and spatial transcriptomics define tumour cell metaprograms and tumour microenvironment organisation in choroid plexus tumours
AU - Anna Klötergens
AU - Clara Inserte
AU - Flavia W. de Faria
AU - Archana Verma
AU - Erik Schüftan
AU - Rajanya Roy
AU - Victor Banerjee
AU - Thomas K. Albert
AU - I-Na Lu
AU - Uwe Kordes
AU - Denise Obrecht-Sturm
AU - Christian Thomas
AU - Kornelius Kerl
PY - 2026
DA - 2026/11/03
JO - Genome Medicine
DO - 10.1186/s13073-026-01814-8
UR - https://doi.org/10.1186/s13073-026-01814-8
AB - Background: Choroid plexus tumours (CPTs) are rare intraventricular brain neoplasms derived from choroid plexus epithelium, predominantly affecting young children. They include benign choroid plexus papilloma (CPP), atypical CPP (aCPP), and malignant choroid plexus carcinoma (CPC) and segregate into three DNA-methylation subgroups: paediatric A (pedA), paediatric B (pedB), and adult. Methods: To resolve subtype-specific biology, we performed single-nucleus RNA sequencing on 43 CPTs and integrated 12 non-neoplastic foetal, paediatric, and adult choroid plexus references, complemented by spatial transcriptomics in a subset of 16 tumour sections and 2 normal choroid plexus samples. Results: Tumour embeddings and correlation analyses demonstrated that CPTs cluster by methylation subtype rather than WHO grade, revealing epigenetically driven relationships despite divergent histology. We identified 10 tumour metaprograms spanning epithelial differentiation, ciliogenesis, proliferation, extra cellular matrix remodelling, and stress responses. PedA and adult tumours showed relatively homogeneous program distribution dominated by differentiation or ciliation states, whereas pedB tumours exhibited marked heterogeneity with selective enrichment of hypoxia, interferon signalling, early stress response, and TGF-β signalling. Spatial mapping revealed consistent anticorrelation of these programs with ciliogenesis and differentiation programs, suggesting stress-associated dedifferentiation. Elevated stress and hypoxia scores correlated with poorer survival. PedB tumours showed enrichment of interferon- and lipid-associated myeloid populations, that carried pro-angiogenic signatures. They were spatially co-localised with hypoxic and interferon I expressing tumour areas, that were predicted to interact with myeloid cells via immunosuppressive cues, shaping a pro-angiogenic, pro-tumour environment. Conclusions: This study identifies stress- and hypoxia-associated dedifferentiation programs that are selectively enriched in pedB tumours, correlate with poor clinical outcome, and antagonise multiciliogenesis and epithelial differentiation. Their spatial co-localisation with immunosuppressive, pro-angiogenic macrophage populations links developmental arrest to microenvironmental remodelling and aggressive behaviour. These findings provide a biologically grounded framework for risk stratification and highlight hypoxia, angiogenesis and macrophage polarisation as candidate therapeutic targets in high-risk CPTs. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13073-026-01814-8.
SN - 1756-994X
ER -