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RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

ABSTRACT: RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

PROVIDER: PRJNA822643 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18583900.fastq.gz	Fastqsanger.gz
	SRR18583901.fastq.gz	Fastqsanger.gz
	SRR18583902.fastq.gz	Fastqsanger.gz
	SRR18583903.fastq.gz	Fastqsanger.gz
	SRR18583904.fastq.gz	Fastqsanger.gz

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RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

Project description:DNA methylation is frequently disrupted in sarcoma but little is known about the specific roles of DNA methyltransferases (DNMTs) in this process. Using an shRNA lentivirus-mediated genetic depletion approach, we found that reduction of DNMT3A or DNMT3B expression potently reduced UPS cell proliferation. Therefore, we performed RNA sequencing to identify global gene expression changes in DNMT3A- or DNMT3B-depleted cells.

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Project description:Undifferentiated pleomorphic sarcomas (UPS) are thought to harbor a small population of cells with unique capability of tumor initiation and maintenance. These tumor initiating cells (TICs) are regarded as the drivers of cancer progression. However, the evidence for this tumor initiating cell (TIC) concept is based on the xenotransplantation assays in mice and the clinical relevance of the TIC concept remains unclear in UPS. We hypothesized that the distinct properties of the TICs would be reflected in the clinical outcome if the TIC concept is relevant in UPS. Here we performed global gene expression profiling of TIC-enriched side population (SP) fractions and non-SP fractions sorted from 15 UPS primary samples. Ninety-three genes were differentially expressed in between SP fractions and non-SP fractions. The UPS TIC gene expression signature score summarizing expression of these genes was calculated for a gene expression data and was correlated with clinical outcome. In the 15 samples used to generate the signature, patients with high scores in the SP fractions were associated with worse survival. We then tested the two independent published datasets with gene expression data on bulk unsorted samples, assuming that the TIC gene expression would persist in the non-TICs. Patients with high scores had significantly worse metastasis-free survival in both datasets. The significance of the score remained significant even considering for the known prognostic factor of UPS. Thus, gene expression signature derived from UPS TICs predicts clinical outcome, suggesting the clinical relevance of the TIC concept in UPS.

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Project description:Although radiotherapy plays a crucial role in treating many cancers, the effect of radiation on tumor evolution remains unclear. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA (ctDNA) analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPS displayed initial linear evolution followed by subsequent branching evolution with distinct mutational processes during early and late development. Using metrics of genetic divergence between regions, we demonstrated evidence of strong selection pressures during UPS development that further increased during radiotherapy. We observed changes in subclone abundance following radiotherapy with subclone contraction tied to alterations in calcium signaling and demonstrated that inhibiting calcium transporters can radiosensitize sarcoma cells. Finally, ctDNA analysis accurately measured subclone abundance and enabled non-invasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPS and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy.

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