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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells

ABSTRACT: Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells

PROVIDER: PRJNA1046113 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26961641_1.fastq.gz	Fastqsanger.gz
	SRR26961641_2.fastq.gz	Fastqsanger.gz
	SRR26961642_1.fastq.gz	Fastqsanger.gz
	SRR26961642_2.fastq.gz	Fastqsanger.gz
	SRR26961643_1.fastq.gz	Fastqsanger.gz

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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [ATAC-seq]

Project description:Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [ATAC-seq]

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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [scRNA-seq]

Project description:Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [scRNA-seq]

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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [RNA-seq]

Project description:Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [RNA-seq]

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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [ATAC-seq]

Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy, while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks including 4,444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1 regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance making its inhibition a promising target for future combination therapy.

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Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [scRNA-seq]

2023-12-01 | GSE248856 | GEO

Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [RNA-seq]

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Desmoplastic small round cell tumor is dependent on EWS-WT1

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Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1-WT1 chimeric transcription factor. Despite this unique oncogenic driver, DSRCT displays a polyphenotypic differentiation of unknown causality. Using single-cell multi-omics on samples from patients, we find that DSRCT tumor cells cluster into consistant subpopulations with partially overlapping lineage- and metabolism-related transcriptional programs.

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Project description:This dataset comprises single-cell RNA-sequencing data of two orthotopically xenografted desmoplastic small round cell tumor (DSRCT) cell lines (JN-DSRCT-1 and SK-DSRCT2) after posttranscriptional knockdown of EWSR1::WT1 fusion oncogene.

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