Human pluripotent stem cell-derived brain tumor model uncovered embryonic stem cell signature as a key driver in atypical teratoid/rhabdoid tumor (RNA-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118654 | GEO | 2019/06/20
REPOSITORIES: GEO
Similar Datasets
Project description:Atypical teratoid/rhabdoid tumor (AT/RT), which harbors INI1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here we established human INI1-deficient pluripotent stem cells (hPSCs), which developed AT/RT formation in vivo. However, INI1-deficient hPSC-derived neural progenitor cell (NPC) gave rise to mostly medulloblastoma-like tumors when transplanted into the mouse brain.
2019-06-20 | GSE118653 | GEO
Project description:Pediatric embryonal brain tumor (PEBT), which includes medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), is the second most prevalent pediatric tumor type among brain tumors of childhood. AT/RT is highly malignant and is often misdiagnosed as MB and PNET. Distinguishing AT/RT from PNET/MB is of clinical significance since the survival rate of AT/RT patients is much lower. The diagnosis of AT/RT relies primarily on the morphologic assessment and immunohistochemistry (IHC) staining on a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we observed several AT/RT-like tumors, which fulfilled histopathologic and all other biomarker criteria for AT/RT diagnosis, still showed retained INI1 immunoreactivity. Recent studies also reported retained INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases. Sanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples for studying their genomics landscapes. AT/RT and INI(+) AT/RT-like patients had similar survival rate, and global array CGH analysis and INI1 gene sequencing showed there is no differential chromosomal aberration marker between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MB or PNET as AT/RT-like cases since transcriptome profiling revealed that not only AT/RT and INI(+) AT/RT-like cases expressed distinct mRNA and microRNA profiles, and their gene expression patterns were different from those of MBs and PNETs. AT/RTs shared the closest transcriptome profile to embryonic stem cells, INI1(+) AT/RT-like tumors were more similar to somatic neural stem cell, while MBs were closer to fetal brain. Novel biomarkers were identified to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs. Our studies disclosed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric cases. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome information unveiled in this work. 2 AT/RT-like cases and 7 AT/RT cases are subjected to transcriptome analysis.
2015-01-22 | E-GEOD-65132 | biostudies-arrayexpress
Project description:Pediatric embryonal brain tumor (PEBT), which includes medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), is the second most prevalent pediatric tumor type among brain tumors of childhood. AT/RT is highly malignant and is often misdiagnosed as MB and PNET. Distinguishing AT/RT from PNET/MB is of clinical significance since the survival rate of AT/RT patients is much lower. The diagnosis of AT/RT relies primarily on the morphologic assessment and immunohistochemistry (IHC) staining on a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we observed several AT/RT-like tumors, which fulfilled histopathologic and all other biomarker criteria for AT/RT diagnosis, still showed retained INI1 immunoreactivity. Recent studies also reported retained INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases. Sanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples for studying their genomics landscapes. AT/RT and INI(+) AT/RT-like patients had similar survival rate, and global array CGH analysis and INI1 gene sequencing showed there is no differential chromosomal aberration marker between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MB or PNET as AT/RT-like cases since transcriptome profiling revealed that not only AT/RT and INI(+) AT/RT-like cases expressed distinct mRNA and microRNA profiles, and their gene expression patterns were different from those of MBs and PNETs. AT/RTs shared the closest transcriptome profile to embryonic stem cells, INI1(+) AT/RT-like tumors were more similar to somatic neural stem cell, while MBs were closer to fetal brain. Novel biomarkers were identified to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs. Our studies disclosed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric cases. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome information unveiled in this work.
2015-01-22 | GSE65132 | GEO
Project description:Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS-tumors of infancy and early childhood. Hallmark is the surprisingly simple genomics with a truncating mutation in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T-cells. However, it is unclear, what T-cells might recognize on AT/RT cells. Here, we report a comprehensive analysis of naturally presented HLA-class-I and class-II ligands on n=23 AT/RTs. MS-based analysis of the HLA-ligandome revealed 55 class-I and 139 class-II peptides from tumor-associated proteins.
2022-05-31 | PXD033935 | Pride
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.
2022-10-14 | PXD027211 | Pride
Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development.
2013-12-31 | GSE46017 | GEO
Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes
2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.
2022-09-19 | GSE179668 | GEO
Project description:Molecular profiling of tumors has proven a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas and other cancers. However, the molecular landscape of atypical teratoid / rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs, and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to gender, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of choroid plexus genes in Cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean 4.7 months) in both Clusters 3 and 4 compared to Clusters 1 and 2 (mean 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were up-regulated in the short survival clusters, with BMP4 showing the most significant up-regulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist within AT/RTs, and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic and therapeutic value. Key Words: atypical teratoid / rhabdoid tumor; bone morphogenetic protein pathway; BMP4; survival; microarray Molecular profiling of 18 AT/RT patient tumor samples was performed using Affymetrix U133 Plus2 GeneChips. Data were background corrected and normalized using gcRMA (as implemented in Bioconductor). Unsupervised agglomerative hierarchical clustering was performed to identify subsets of AT/RTs with similar gene expression. Limma (moderated t-tests; Bioconductor) was used to identify signature genes for each cluster. Bioinformatics web tool DAVID was used to identify enriched biological processes for each cluster. Survival was analyzed using Kaplan-Meier curves and Cox Hazard Ratio. Bioinformatics tools Gene Set Enrichment (GSEA) and Ingenuity Pathways Analysis were also used to gain further insight into cluster differences.
2011-09-21 | E-GEOD-28026 | biostudies-arrayexpress
Project description:Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness, exceptionally low mutation rate, and aberrant but still unresolved epigenetic regulation. To evaluate methylation associated regulation in AT/RTs, we compared them to medulloblastomas and choroid plexus tumors by integrating DNA methylation (507 samples), gene expression (120 samples), and public transcription factor (TF) binding data. We showed that elevated DNA methylation masks the binding sites of TFs driving neural development and is associated with reduced transcription for specific neural regulators in AT/RTs. Hypermethylated sites largely behaved similarly in AT/RTs and pluripotent stem cells, revealing DNA methylation -driven halted cell differentiation. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 members, like EZH2, and linked to suppressed genes with a role in neural development and tumorigenesis. The obtained results highlight and characterize these DNA methylation programs as drivers of AT/RT malignancy.
2024-03-04 | GSE197569 | GEO