Single-cell RNA sequencing analysis reveals CHOP as an early marker for conventional chondrosarcoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184118 | GEO | 2024/01/18
REPOSITORIES: GEO
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Project description:Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. We aimed to uncover the transcriptional program directing such tumor progression in chondrosarcomas. Here, we conducted weighted correlation network analysis (WGCNA) to extract a characteristic gene module underlying chondrosarcoma malignancy. We identified hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) as an upstream regulator that governs the malignancy gene module. HIF-2α was upregulated in high grade chondrosarcoma biopsies and HIF-2α gene amplification was associated with the poor prognosis of patients with chondrosarcoma. Using tumor xenograft mouse models, we demonstrated that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Pharmacological inhibition of HIF-2α in conjunction with the chemotherapy agents synergistically enhanced chondrosarcoma cell apoptosis and abolished malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of novel molecular-targeted therapeutics for chondrosarcoma.
2020-08-21 | GSE156565 | GEO
Project description:Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed lesions similar to chondrosarcomas when also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and IGF signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limbs explants with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when also deficient for Igf2. IGF signaling meditated apoptosis regulates the progression to malignant chondrosarcoma.
2009-03-06 | GSE15118 | GEO
Project description:Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1–HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.
2023-12-01 | GSE248490 | GEO
Project description:In this study, a series of 102 cartilage tumors was used to uncover the molecular diversity of chondrosarcomas through the profiling of mRNA, miRNA, DNA methylation, DNA copy number aberrations and point mutations. An integrated classification using multiple molecular dimensions revealed three major molecular features unraveling the diversity in clinical outcome of chondrosarcoma: a high mitotic state, regional 14q32 loss of expression and IDH mutations leading to genome-wide hypermethylation. These three robust and simple molecular features classify chondrosarcoma in subtypes with superior clinical value as compared to the current grading system.
2019-07-19 | E-MTAB-7264 | biostudies-arrayexpress
Project description:In this study, a series of 102 cartilage tumors was used to uncover the molecular diversity of chondrosarcomas through the profiling of mRNA, miRNA, DNA methylation, DNA copy number aberrations and point mutations. An integrated classification using multiple molecular dimensions revealed three major molecular features unraveling the diversity in clinical outcome of chondrosarcoma: a high mitotic state, regional 14q32 loss of expression and IDH mutations leading to genome-wide hypermethylation. These three robust and simple molecular features classify chondrosarcoma in subtypes with superior clinical value as compared to the current grading system.
2019-07-19 | E-MTAB-7263 | biostudies-arrayexpress
Project description:In this study, a series of 102 cartilage tumors was used to uncover the molecular diversity of chondrosarcomas through the profiling of mRNA, miRNA, DNA methylation, DNA copy number aberrations and point mutations. An integrated classification using multiple molecular dimensions revealed three major molecular features unraveling the diversity in clinical outcome of chondrosarcoma: a high mitotic state, regional 14q32 loss of expression and IDH mutations leading to genome-wide hypermethylation. These three robust and simple molecular features classify chondrosarcoma in subtypes with superior clinical value as compared to the current grading system.
2019-07-19 | E-MTAB-7265 | biostudies-arrayexpress
Project description:In this study, a series of 102 cartilage tumors was used to uncover the molecular diversity of chondrosarcomas through the profiling of mRNA, miRNA, DNA methylation, DNA copy number aberrations and point mutations. An integrated classification using multiple molecular dimensions revealed three major molecular features unraveling the diversity in clinical outcome of chondrosarcoma: a high mitotic state, regional 14q32 loss of expression and IDH mutations leading to genome-wide hypermethylation. These three robust and simple molecular features classify chondrosarcoma in subtypes with superior clinical value as compared to the current grading system.
2019-08-05 | E-MTAB-8213 | biostudies-arrayexpress
Project description:Here we have used four enchondromas and two chondrosarcomas of Maffucci patients. We also had one normal sample available for paired analysis in one of the chondrosarcoma II. We did not find any LOH or coomon copy number variation in all Maffucci enchondromas while chondrosarcomas are genetically unstable.
2011-07-19 | GSE26674 | GEO
Project description:Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events.
2011-09-26 | GSE25985 | GEO
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program. We used microarrays to detail the global program of gene expression in mouse mesenchymal chondrosarcoma
2023-09-11 | GSE163291 | GEO