Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
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PROVIDER: EGAS00001004349 | EGA |
REPOSITORIES: EGA
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Project description:94 sample with multi-omics analysis of ALT-positive neuroblastoma tumors, rna sequencing
| EGAD00001006587 | EGA
Project description:Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.
| S-EPMC7904810 | biostudies-literature
Project description:Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. Based on our results we here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically evaluate telomere maintenance mechanisms in risk stratification and treatment allocation of neuroblastoma patients.
2022-09-19 | GSE211653 | GEO
Project description:Neuroblastoma, a deadly pediatric cancer from the sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes in high-risk cases. While primary tumors are well-characterized, the cellular and molecular dynamics of metastasis remain poorly understood. Here, we employed single-cell multi-omics and spatial transcriptomics to profile lymph node metastases in high-risk neuroblastoma compared to primary adrenal masses. We found that lymph node metastases displayed unique cellular heterogeneity and plasticity marked by a shift toward mesenchymal-like and cancer stem cell states, with enriched epithelial-to-mesenchymal transition (EMT) programs. Lymph node metastatic niche exhibited altered tumor microenvironment dynamics, characterized by increased immunosuppressive myeloid subsets, heightened immune checkpoint signaling and lymphocyte exhaustion, indicative of immune evasion and dysfunction. Our multi-omics studies reveal distinct features of high-risk neuroblastoma that contribute to metastasis and therapy resistance, pointing to potential therapeutic vulnerabilities of the aggressive metastatic disease.
2026-02-18 | GSE309269 | GEO
Project description:Neuroblastoma, a deadly pediatric cancer from the sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes in high-risk cases. While primary tumors are well-characterized, the cellular and molecular dynamics of metastasis remain poorly understood. Here, we employed single-cell multi-omics and spatial transcriptomics to profile lymph node metastases in high-risk neuroblastoma compared to primary adrenal masses. We found that lymph node metastases displayed unique cellular heterogeneity and plasticity marked by a shift toward mesenchymal-like and cancer stem cell states, with enriched epithelial-to-mesenchymal transition (EMT) programs. Lymph node metastatic niche exhibited altered tumor microenvironment dynamics, characterized by increased immunosuppressive myeloid subsets, heightened immune checkpoint signaling and lymphocyte exhaustion, indicative of immune evasion and dysfunction. Our multi-omics studies reveal distinct features of high-risk neuroblastoma that contribute to metastasis and therapy resistance, pointing to potential therapeutic vulnerabilities of the aggressive metastatic disease.
2026-02-18 | GSE309268 | GEO
Project description:Neuroblastoma, a deadly pediatric cancer from the sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes in high-risk cases. While primary tumors are well-characterized, the cellular and molecular dynamics of metastasis remain poorly understood. Here, we employed single-cell multi-omics and spatial transcriptomics to profile lymph node metastases in high-risk neuroblastoma compared to primary adrenal masses. We found that lymph node metastases displayed unique cellular heterogeneity and plasticity marked by a shift toward mesenchymal-like and cancer stem cell states, with enriched epithelial-to-mesenchymal transition (EMT) programs. Lymph node metastatic niche exhibited altered tumor microenvironment dynamics, characterized by increased immunosuppressive myeloid subsets, heightened immune checkpoint signaling and lymphocyte exhaustion, indicative of immune evasion and dysfunction. Our multi-omics studies reveal distinct features of high-risk neuroblastoma that contribute to metastasis and therapy resistance, pointing to potential therapeutic vulnerabilities of the aggressive metastatic disease.
2026-02-18 | GSE309267 | GEO
Project description:The aim of this study is to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pre-treatment neuroblastoma, and to assess the potential value of telomerase as a therapeutic target. Therefore, the genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence-in-situ-hybridization. ALT was examined in 273/457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by 4x44k microarrays in 223 of these. The presence of activated telomerase, i.e., TERT rearrangements, MYCN amplification, or high TERT expression without these alterations, was associated with poorest overall survival, and was an independent prognostic marker in multivariable analyses.
2019-09-16 | E-MTAB-8248 | biostudies-arrayexpress
Project description:The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive carcinoma cell line.
2019-09-25 | GSE129448 | GEO
Project description:Alternative lengthening of telomeres (ALT) supports telomere maintenance and replicative immortality in around 10-15% of cancers, thus representing a compelling target for therapy.To identify anti-cancer drugs that can be repurposed as ALT-centered therapies, we performed for a compound library screen on isogenic cell lines that rely either on telomerase or ALT mechanisms. We validated candidates on a panel of ALT- vs. telomerase-positive sarcoma cells and assessed levels of extrachromosomal telomeric C-circles after drug treatment, as a bona fide marker of ALT activity. We identified a receptor tyrosine kinase inhibitor ponatinib that deregulated ALT mechanisms, increased telomeric replicative stress and induced telomeric dysfunction in ALT cells. Using a model of ALT sarcoma xenografts, we found that ponatinib targeted ALT-positive cells and mitigated telomere elongation in these tumors. To identify the mode of action of ponatinib on ALT, we performed RNA-sequencing and quantitative proteomic and phosphoproteomic analyses, and shortlisted candidates to test the effect of their loss on telomeric C-circle levels. We identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor.
2023-02-20 | PXD037501 | Pride
Project description:89 samples of individuals with ALT-positive neuroblastoma tumors, exome sequencing
| EGAD00001006637 | EGA