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Childhood brain tumors instructs cranial haematopoiesis and immunotolerance

ABSTRACT: ZFTA-RELA ependymoma poses a formidable challenge due to limited treatment avenues, prompting exploration into immunotherapeutic approaches. Recent investigations have shed light on the calvaria bone marrow as a source of meningeal immune cells crucial for central nervous system (CNS) immunity. Whether or not cues from the tumour microenvironment can instruct local haematopoiesis within the skull is unknown. We used single cell RNA sequencing (snRNAseq + snATAC) to analyze the dynamic transcriptional regulation of skull, peripheral bone marrow from tumour-bearing and non-tumour bearing ZFTA-RELA fusion driven ependymoma mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE282459 | GEO | 2025/12/01

REPOSITORIES: GEO

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Ependymoma instructs cranial haematopoiesis and immunotolerance

Project description:ZFTA-RELA ependymoma presents a significant clinical challenge due to the lack of effective treatments, driving the need to explore novel immunotherapeutic strategies. Recent studies have identified the skull bone marrow as a source of meningeal immune cells critical for central nervous system (CNS) immunity, yet the role of these cells in childhood CNS tumour surveillance and pathology remains unclear. Here, we demonstrate that intracranial childhood ependymoma tumours harbour a unique myeloid cell population, including hematopoietic stem cells (HSCs) not from the blood, but supplied by adjacent skull bone marrow, ontogenetically distinct from their blood-derived counterparts. Our findings challenge the conventional view of HSCs as passive players in the CNS, revealing that antigen-specific interactions between skull bone marrow-derived HSCs and CD4+ T cells actively promote immunotolerance in childhood brain tumours by enhancing local myelopoiesis and inducing regulatory T cell polarization. This work uncovers a previously unrecognized cellular network linking the skull to brain tumours in children and underscores the therapeutic potential of modulating skull bone marrow haematopoiesis to shift the local immune environment. Targeting this skull-specific immune pathway offers a promising avenue for developing localized immunotherapies to improve treatment outcomes.

2025-12-01 | PXD058239 | Pride

Childhood brain tumours instruct cranial haematopoiesis and immunotolerance [scRNAseqTCR postTx]

Project description:Recent research has revealed a remarkable role for immunosurveillance in healthy and diseased brains, dispelling the notion that this organ is a passive immune-privileged site. Better understanding of how this immunosurveillance operates could improve the treatment of neurological diseases. Here, using a novel genetically engineered mouse model of ZFTA-RELA ependymoma–a childhood brain tumour–we characterised an immune circuit between the tumour and antigen presenting, haematopoietic stem/progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens in the cerebrospinal fluid (CSF) by HSPCs to CD4+ T cells, biased HSPCs lineages toward myelopoiesis and polarised CD4+ T-cells to regulatory T cells (T-regs), culminating in tumour immunotolerance. Remarkably, a single infusion of antibodies directed against cytokines enriched in the CSF of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or Group-3 medulloblastoma–all aggressive childhood brain tumours–disrupted this process and caused profound tumour regression. These data unmask a mechanism by which skull bone marrow-derived HSPCs and CD4+ T cells cooperate to promote the immunotolerance of childhood brain tumours. Antibodies that disrupt this immunosurveillance could prove an effective therapy for these cancers that are less toxic than current treatments.

2025-12-01 | GSE300890 | GEO

Ependymoma instructs cranial haematopoiesis and immunotolerance

Project description:ZFTA-RELA ependymoma presents a significant clinical challenge due to the lack of effective treatments, driving the need to explore novel immunotherapeutic strategies. Recent studies have identified the skull bone marrow as a source of meningeal immune cells critical for central nervous system (CNS) immunity, yet the role of these cells in childhood CNS tumor surveillance and pathology remains unclear. Here, we demonstrate that intracranial childhood ependymoma tumors harbour a unique myeloid cell population, including hematopoietic stem cells (HSCs) not from the blood, but supplied by adjacent skull bone marrow, ontogenetically distinct from their blood-derived counterparts. Our findings challenge the conventional view of HSCs as passive players in the CNS, revealing that antigen-specific interactions between skull bone marrow-derived HSCs and CD4+ T cells actively promote immunotolerance in childhood brain tumors by enhancing local myelopoiesis and inducing regulatory T cell polarization. This work uncovers a previously unrecognized cellular network linking the skull to brain tumors in children and underscores the therapeutic potential of modulating skull bone marrow haematopoiesis to shift the local immune environment. Targeting this skull-specific immune pathway offers a promising avenue for developing localized immunotherapies to improve treatment outcomes.

2025-12-01 | GSE282337 | GEO

Childhood brain tumors instruct cranial haematopoiesis and immunotolerance [endpoint Fus1 GEX]

Project description:Recent research has revealed a remarkable role for immunosurveillance in healthy and diseased brains, dispelling the notion that this organ is a passive immune-privileged site1–3. Better understanding of how this immunosurveillance operates could improve the treatment of neurological diseases. Here, using a novel genetically engineered mouse model of ZFTA-RELA ependymoma4–a childhood brain tumour–we characterised an immune circuit between the tumour and antigen presenting, haematopoietic stem/progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens in the cerebrospinal fluid (CSF) by HSPCs to CD4+ T cells, biased HSPCs lineages toward myelopoiesis and polarised CD4+ T-cells to regulatory T cells (T-regs), culminating in tumour immunotolerance. Remarkably, a single infusion of antibodies directed against cytokines enriched in the CSF of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or Group-3 medulloblastoma–all aggressive childhood brain tumours–disrupted this process and caused profound tumour regression. These data unmask a mechanism by which skull bone marrow-derived HSPCs and CD4+ T cells cooperate to promote the immunotolerance of childhood brain tumours. Antibodies that disrupt this immunosurveillance could prove an effective therapy for these cancers that are less toxic than current treatments.

2025-12-01 | GSE300889 | GEO

Histone serotonylation regulates ependymoma tumorigenesis through neurodevelopmental pathways [ChIP-Seq]

Project description:To profile H3K4me3Q5Ser (5HT-H3) distribution in mouse ZFTA-RELA ependymoma tumors Furthermore, we also sought to examine H3K27ac and H3K27me3 distribution in mouse ZFTA-RELA ependymoma versus ETV5 overexpressing tumors

2024-06-03 | GSE246032 | GEO

Histone serotonylation regulates ependymoma tumorigenesis through neurodevelopmental pathways [RNA-seq]

Project description:To profile gene expression differences between mouse non-tumor cortex versus ZFTA-RELA ependymoma versus ETV5 overexpressing tumors Furthermore, we also sought to profile gene expression differences between ZFTA-RELA ependymoma versus NPY overexpressing tumor

2024-06-03 | GSE246031 | GEO

Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

Project description:Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). Yet, how the calvaria bone marrow is different from the other bones and whether it plays a special role in human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific outcomes including increased calvaria cell numbers. Moreover, TSPO-PET imaging of stroke, dementia and multiple sclerosis patients demonstrate increased inflammation in the human skull, mirroring the underlying brain inflammation.

2024-01-17 | PXD030250 | Pride

Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in in mice and humans

Project description:The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The mouse calvaria and the human skull harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins when compared to other bones. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies.

2023-07-29 | PXD041665 | Pride

Ependymoma instructs cranial haematopoiesis and immunotolerance

Project description:Ependymoma instructs cranial haematopoiesis and immunotolerance

| PRJNA1188159 | ENA

ZFTA-RELA ependymomas produce itaconate as an oncometabolite to sustain pathogenic fusion expression [ATAC-Seq]

Project description:ZFTA-RELA ependymomas are malignant brain tumors that are frequently lethal. They are defined by fusions formed between the putative chromatin remodeler ZFTA and the NFkB-mediator-RELA. We identified that ZFTA-RELA cells produced itaconate, a key macrophage-associated immunomodulator metabolite. However, itaconate production by tumor cells and its tumor-intrinsic role are not well-established. Itaconate is synthesized by the enzyme Aconitate Decarboxylase-1 (ACOD1) and the ZFTA-RELA fusion upregulated ACOD1 in an NFkB-dependent manner. Additionally, itaconate production enabled a feed-forward system that maintained pathogenic ZFTA-RELA fusion expression through epigenetic activation. To supply the metabolic fuel needed to generate itaconate, these tumors epigenetically activated PI3K/mTOR signaling to enhance glutaminolysis, which provided the carbons necessary for itaconate synthesis. Consequently, antagonizing glutamine metabolism lowered pathogenic ZFTA-RELA levels and was potently therapeutic in multiple in vivo models. Finally, combining glutamine antagonism with PI3K/mTOR inhibition abrogated spinal metastasis. Our data demonstrate that ZFTA-RELA ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA fusion driver, implicating itaconate as an oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA ependymomas. This study therefore has implications for future drug development for children with this devastating brain tumor and will further our understanding of oncometabolites as a novel class of therapeutic dependencies in cancers.

2025-11-17 | GSE294954 | GEO

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