Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time
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PROVIDER: PRJNA935425 | ENA |
REPOSITORIES: ENA
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Project description:Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time
| PRJNA935426 | ENA
Project description:Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict-it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time.SignificanceChromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution.
| S-EPMC10093779 | biostudies-literature
Project description:Osteosarcoma is the most common bone sarcoma in children and young adults. While chemotherapy is universally delivered, benefit from chemotherapy is limited to roughly half of localized patients. Increasingly, intratumoral heterogeneity is being appreciated as a source of therapeutic resistance. In this study we developed and evaluated an in vitro model of osteosarcoma heterogeneity, characterizing phenotype (growth in varying environments, sensitivity to chemotherapy) and genotype. We present the genotypic and phenotypic characterization of an osteosarcoma cell line panel with a focus on coculture of the most phenotypically divergent cell lines, 143B and SAOS2. The extent of phenotypic heterogeneity can be altered with relatively modest environmental (pH, glutamine) or chemical perturbations. We demonstrate that in nutrient rich in vitro culture conditions 143B outcompetes SAOS2, but with selection pressure from nutrient variations or conventional chemotherapy, SAOS2 growth can be favored in spheroids. Importantly, perturbations that affect the faster growing cell line have only a modest effect on final spheroid size when the simplest heterogeneity state (a two-cell line coculture) is evaluated, and thus the only evaluated therapies to eliminate the spheroids were by switching therapies from a first strike to a second strike. This extensively characterized, widely available system can be modeled and scaled to allow for improved strategies to anticipate resistance in osteosarcoma due to phenotypic heterogeneity.
2023-11-22 | GSE240278 | GEO
Project description:CD102- MHCII+ (F4/80lo) resident peritoneal macrophages exhibit limited sexual dimporphism in gene expression
| PRJNA825566 | ENA
Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.
2011-02-22 | GSE24401 | GEO
Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma. Dye balance-experiment comparing atorvastatin versus untreated cells at 6, 15 and 24 hours using 2 biological replicates.
2011-02-22 | E-GEOD-24401 | biostudies-arrayexpress
Project description:Osteosarcoma is the most common primary bone sarcoma. About 50% of patients develop metastatic disease and their 5-year survival lingers at around 20-30%. T cell checkpoint blockade immunotherapies have revolutionized cancer treatment in the last decade, but their impact remains limited in osteosarcoma. In order to reveal potentially novel immunotherapeutic strategies for advanced osteosarcoma, we conducted an immunogenomic characterization of a unique sample set comprising multiple osteosarcoma samples from seven patients, collected throughout the progression of the disease. We performed RNA-sequencing and imaging mass cytometry analysis on those samples to reveal the immunological landscape during osteosarcoma progression. Transcriptional and phenotypical hallmarks of cytotoxic T cell-driven anti-cancer immunity were enriched in metastatic lesions as compared to primary tumors. In parallel, we found a pronounced increase in the expression of cancer testis antigens, particularly MAGEA-related antigens, in osteosarcoma metastases. Their overexpression in metastatic lesions was confirmed at protein level and positive expression of MAGEA3 in primary tumors showed a significant association with metastasis free survival. Importantly, we demonstrated the presentation of MAGE-derived peptides in three osteosarcoma cell lines. These findings indicate a concurrent augmentation of cytotoxic anti-tumor immune responses and expression of MAGEA antigens from primary to metastatic osteosarcoma. This observation warrants the exploration of MAGEA antigens as potential targets for immunotherapy in the treatment of advanced osteosarcoma.
2024-02-07 | GSE237033 | GEO
Project description:Modeling Phenotypic Heterogeneity Towards Evolutionary Inspired Osteosarcoma Therapy
| PRJNA1003084 | ENA
Project description:Prostate cancers exhibit a spectrum of molecular aberrations of which a substantial subset are amenable to targeted therapeutics. To determine the diversity of somatic alterations present in metastasis within and between individuals we characterized the genomic landscapes of 176 tumors acquired from 63 men. In contrast to the considerable variation across individuals, the molecular diversity of tumors within an individual was substantially less: alterations in putative drivers of cancer growth and cell cycle progression status were highly concordant. While androgen receptor activity was inversely related to proliferation, the expression of Fanconi Anemia complex genes was strongly associated with increased cell cycle progression. Inhibition of FANCA, FANCC, FANCD2 and BRCA2 expression reduced prostate cancer growth. The limited molecular diversity across metastases may result from bottlenecks imposed by the dissemination process, limited evolutionary time between metastatic seeding and tumor sampling, intermixing of tumor clones, and selection resulting from treatment pressures. Though exceptions exist, evaluating a single metastasis provides a reasonable assessment of the key molecular processes that occur throughout the spectrum of disseminated tumors within an individual, and may be used for selecting treatments based on predicted molecular vulnerabilities. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 171 CRPC tumors from 63 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2015-12-18 | E-GEOD-74685 | biostudies-arrayexpress
Project description:Circular RNAs exhibit limited evidence for translation, or translation regulation of the mRNA-counterpart in terminal hematopoiesis
| PRJNA669808 | ENA