Single-nucleus and spatial transcriptomics map tumour metaprograms in choroid plexus tumours

Choroid plexus tumours, rare intraventricular brain neoplasms derived from choroid plexus epithelium that predominantly affect young children, have now been mapped at single-cell and spatial resolution in an integrated study published in Genome Medicine. The work combined single-nucleus RNA sequencing of 43 tumours with spatial transcriptomics on 16 tumour sections and 2 normal choroid plexus samples, and it identified ten recurring tumour cell metaprograms whose distribution tracks DNA-methylation subtype rather than World Health Organization grade. The findings also link stress-associated dedifferentiation programs to poor clinical outcome and to a pro-angiogenic, immunosuppressive microenvironment in the most aggressive molecular subgroup.

The tumour types examined span a biological spectrum from benign choroid plexus papilloma through atypical papilloma to malignant choroid plexus carcinoma. Despite these divergent histologies, the study showed that tumours segregate into three DNA-methylation subgroups, termed paediatric A, paediatric B, and adult. Tumour embeddings and correlation analyses demonstrated that the tumours cluster by methylation subtype rather than WHO grade, revealing epigenetically driven relationships that histological classification alone does not capture.

To resolve subtype-specific biology, the researchers performed single-nucleus RNA sequencing on all 43 tumours and integrated the data with 12 non-neoplastic foetal, paediatric, and adult choroid plexus references. This comparative design allowed the team to place malignant cells in the context of normal choroid plexus development across the lifespan. The analysis identified 10 tumour metaprograms spanning epithelial differentiation, ciliogenesis, proliferation, extracellular matrix remodelling, and stress responses, providing a structured catalogue of the transcriptional states that tumour cells occupy.

The distribution of these programs differed sharply between subgroups. Paediatric A and adult tumours showed relatively homogeneous program distribution dominated by differentiation or ciliation states, consistent with tumour cells that largely retain features of mature choroid plexus epithelium. Paediatric B tumours, by contrast, exhibited marked heterogeneity, with selective enrichment of hypoxia, interferon signalling, early stress response, and TGF-β signalling programs. This heterogeneity indicates that individual paediatric B tumours contain mixtures of cells in very different biological states rather than a uniform malignant population.

Spatial transcriptomics added a positional dimension to this picture. Mapping of the programs across tumour sections revealed consistent anticorrelation of the stress-associated states with ciliogenesis and differentiation programs. The authors interpret this spatial pattern as evidence of stress-associated dedifferentiation, in which tumour cells exposed to hostile conditions lose differentiated, ciliated characteristics. Elevated stress and hypoxia scores correlated with poorer survival, connecting this molecular architecture directly to clinical outcome.

The study also characterised the tumour microenvironment in spatial context. Paediatric B tumours showed enrichment of interferon- and lipid-associated myeloid populations that carried pro-angiogenic signatures. These myeloid cells were spatially co-localised with hypoxic and interferon I expressing tumour areas. Computational interaction analysis predicted that tumour cells in these regions communicate with myeloid cells via immunosuppressive cues, shaping a pro-angiogenic, pro-tumour environment. In this model, hypoxic tumour areas do not simply suffer from low oxygen; they appear to recruit and polarise immune cells in ways that may support tumour growth.

The conclusions draw these strands together into a coherent disease model. The study identifies stress- and hypoxia-associated dedifferentiation programs that are selectively enriched in paediatric B 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. In other words, the same transcriptional programs that mark a failure of tumour cells to reach mature, ciliated states also coincide with an immune and vascular milieu that favours tumour progression.

These findings provide a biologically grounded framework for risk stratification in choroid plexus tumours, a disease area where histological grading alone may not fully reflect molecular behaviour. The authors highlight hypoxia, angiogenesis, and macrophage polarisation as candidate therapeutic targets in high-risk tumours, particularly within the paediatric B subgroup where these features converge. Because the study is a single integrated analysis of 43 tumours with spatial profiling in a subset of 16 sections and 2 normal samples, the therapeutic implications remain hypotheses for future testing rather than established treatment options. Nevertheless, the work offers a detailed molecular and spatial atlas that connects epigenetic subgroup, tumour cell state, microenvironmental organisation, and clinical outcome in one of paediatric neuro-oncology’s rarest tumour types.

Subject of Research: Single-cell and spatial transcriptomic profiling of tumour cell metaprograms and microenvironment organisation in choroid plexus tumours

Article Title: Integrated single-nucleus and spatial transcriptomics define tumour cell metaprograms and tumour microenvironment organisation in choroid plexus tumours

Article References: Klötergens, A., Inserte, C., de Faria, F. W., Verma, A., Schüftan, E., Roy, R., Banerjee, V., Albert, T. K., Lu, I.-N., Kordes, U., Obrecht-Sturm, D., Thomas, C., & Kerl, K. (2026). Integrated single-nucleus and spatial transcriptomics define tumour cell metaprograms and tumour microenvironment organisation in choroid plexus tumours. Genome Medicine, 18(1), Article 172. https://doi.org/10.1186/s13073-026-01814-8

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01814-8

Keywords: choroid plexus tumours, single-nucleus RNA sequencing, spatial transcriptomics, tumour metaprograms, DNA methylation subgroups, paediatric B, hypoxia, dedifferentiation, tumour microenvironment, macrophage polarisation, pro-angiogenic signalling, risk stratification