Single nucleus transcriptomics of spinal ependymoma subtypes recognizes intratumoral heterogeneity [methylation]
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PROVIDER: PRJNA1269566 | ENA |
REPOSITORIES: ENA
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Project description:Single nucleus transcriptomics of spinal ependymoma subtypes recognizes intratumoral heterogeneity [snRNA-seq]
| PRJNA1269562 | ENA
Project description:The two most prevalent types of spinal ependymal tumors are myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN). Based on molecular data from bulk tumor samples, we previously identified clinically relevant subtypes with poor (MPE-A; SP-EPN-A) and favorable progression-free survival (MPE-B; SP-EPN-B). However, detailed cellular compositions, molecular heterogeneity, and features of tumor progression are largely unknown. We performed single nucleus transcriptomic sequencing of 25 formalin-fixed and paraffin-embedded spinal ependymal tumors including all MPE and SP-EPN subtypes as well as six paired primary and relapsed MPE-A. Ependymoma subtypes presented with a broad, but comparable tumor microenvironment. Furthermore, neoplastic cells demonstrated inter- and intratumoral heterogeneity regarding cancer cell state composition. Overall, MPE tumors exhibited a significantly higher abundance of the astrocytic state, whereas a ciliated state was more prevalent in SP-EPN. Also, transcriptome-inferred copy number profiles revealed tumor cell clusters with distinct chromosomal alterations across tumors, suggesting subclonal neoplastic growth. Compared to normal human spinal cord cell populations, MPE tumor cells displayed similarities to astrocytes and ependymal cells, whereas SP-EPN exclusively matched ependymal cells. MPE-A demonstrated a distinct profile, being similar to the roof and floor plate of the developing spinal cord. Paired primary and relapsed MPE-A revealed mostly similar histology, epigenetics, copy number profiles, and cellular composition of neoplastic cells. Single nucleus transcriptomic sequencing provides valuable insights into the molecular composition of spinal ependymoma types and subtypes and may pave the way for a better understanding of tumor evolution and identification of therapeutic targets.
2025-09-12 | GSE298506 | GEO
Project description:The two most prevalent types of spinal ependymal tumors are myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN). Based on molecular data from bulk tumor samples, we previously identified clinically relevant subtypes with poor (MPE-A; SP-EPN-A) and favorable progression-free survival (MPE-B; SP-EPN-B). However, detailed cellular compositions, molecular heterogeneity, and features of tumor progression are largely unknown. We performed single nucleus transcriptomic sequencing of 25 formalin-fixed and paraffin-embedded spinal ependymal tumors including all MPE and SP-EPN subtypes as well as six paired primary and relapsed MPE-A. Ependymoma subtypes presented with a broad, but comparable tumor microenvironment. Furthermore, neoplastic cells demonstrated inter- and intratumoral heterogeneity regarding cancer cell state composition. Overall, MPE tumors exhibited a significantly higher abundance of the astrocytic state, whereas a ciliated state was more prevalent in SP-EPN. Also, transcriptome-inferred copy number profiles revealed tumor cell clusters with distinct chromosomal alterations across tumors, suggesting subclonal neoplastic growth. Compared to normal human spinal cord cell populations, MPE tumor cells displayed similarities to astrocytes and ependymal cells, whereas SP-EPN exclusively matched ependymal cells. MPE-A demonstrated a distinct profile, being similar to the roof and floor plate of the developing spinal cord. Paired primary and relapsed MPE-A revealed mostly similar histology, epigenetics, copy number profiles, and cellular composition of neoplastic cells. Single nucleus transcriptomic sequencing provides valuable insights into the molecular composition of spinal ependymoma types and subtypes and may pave the way for a better understanding of tumor evolution and identification of therapeutic targets.
2025-09-12 | GSE298501 | GEO
Project description:Purpose: Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production. Results: At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. RNA from 35 primary spinal ependymomas (fresh frozen) were isolated by pulverization in liquid nitrogen, and extraction using the Trizol Method (Invitrogen) [PMID:21840481]
2015-09-02 | E-GEOD-66787 | biostudies-arrayexpress
Project description:Ependymoma (EPN) is a type of brain tumour.. Here we present a novel subtype of spinal ependymoma, that shows an anaplastic morphology, OLIG2 and MYCN positvity in immunostaining and a distinct epigenetic and proteomic profile.
2024-05-22 | GSE264714 | GEO
Project description:Purpose: Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production. Results: At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
2015-09-02 | GSE66787 | GEO
Project description:Background: Ependymomas encompass multiple, clinically relevant tumor types based on localization and molecular profiles. Although tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical meaning have been described in a large, epigenetically defined series. Methods: We mapped SP-EPN transcriptomes (n=76) to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. In addition, transcriptomic, epigenetic (n=234), genetic (n=140), and clinical analyses (n=115) were integrated for a detailed overview on this entity. Results: Integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord identified mature adult ependymal cells to display highest similarities to SP-EPN. Unsupervised hierarchical clustering of tumor data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype 1 predominantly contained NF2 wild type sequences with regular NF2 expression but revealed more extensive copy number alterations. Subtype 2 harbored previously known germline or sporadic NF2 mutations and was NF2-deficient in most cases, more often showed multilocular disease, and demonstrated a significantly reduced progression-free survival. Conclusion: Based on integrated molecular profiling of a large tumor series we identify two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.
2024-01-26 | GSE242991 | GEO
Project description:A novel type of spinal ependymoma with anaplastic features
| PRJNA1103838 | ENA
Project description:Spinal ependymomas are the most common spinal cord tumors in adults, but their intratumoral cellular heterogeneity has been less studied, and how spinal microglia are involved in tumor progression is still unknown. Here, our single-cell RNA-sequencing analyses of three spinal ependymoma subtypes dissect the microenvironmental landscape of spinal ependymomas and reveal tumor-associated macrophage (TAM) subsets with distinct functional phenotypes. CCL2+ TAMs are related to the immune response and exhibit a high capacity for apoptosis, while CD44+ TAMs are associated with tumor angiogenesis. By combining these results with those of single-cell ATAC-sequencing data analysis, we reveal that TEAD1 and EGR3 play roles in regulating the functional diversity of TAMs. We further identify diverse characteristics of both malignant cells and TAMs that might underlie the different malignant degrees of each subtype. Finally, assessment of cell-cell interactions reveal that stromal cells act as extracellular factors that mediate TAM diversity. Overall, our results reveal dual functions of TAMs in tumor progression, providing valuable insights for TAM-targeting immunotherapy.
2021-09-28 | GSE163686 | GEO
Project description:Ependymomas of the spinal cord are rare among children and adolescents, and the individual risk of disease progression is difficult to predict. This study aims at evaluating the prognostic impact of molecular typing of pediatric spinal cord ependymomas. Eighty-three patients with spinal ependymomas ≦ 22 years registered in the HIT-MED database between 1992 and 2022 were included. Forty-seven tumors were analyzed by DNA methylation array profiling. In six cases, HOXB13 and MYCN proteins were detected as surrogate markers for specific methylation classes. With a median follow-up time of 4.9 years (y), 5y- and 10y-overall survival (OS) were 100% and 86%, while 5y- and 10y-progression-free survival (PFS) were 65% and 54%. Myxopapillary ependymoma (SP-MPE, n=32, 63%) was the most common molecular type followed by spinal ependymoma (SP-EPN, n=17, 33%) and MYCN-amplified ependymoma (n=2, 4%). One case could not be molecularly classified, and one was reclassified as anaplastic pilocytic astrocytoma. 5y-PFS did not significantly differ between SP-MPE and SP-EPN (65% versus 78%, p=0.64). MYCN-amplification was associated with early relapses (<2.3y) in both cases and death in one patient. Patients with SP-MPE subtype B (n=9) showed a non-significant trend for better 5y-PFS compared to subtype A (n=18; 86% versus 56%, p=0.15). The extent of resection and WHO tumor grades significantly influenced PFS in a uni- and multivariate analysis.
2024-10-23 | GSE276972 | GEO