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Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

ABSTRACT: Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

PROVIDER: PRJNA704753 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13781700_1.fastq.gz	Fastqsanger.gz
	SRR13781700_2.fastq.gz	Fastqsanger.gz
	SRR13781701_1.fastq.gz	Fastqsanger.gz
	SRR13781701_2.fastq.gz	Fastqsanger.gz
	SRR13781702_1.fastq.gz	Fastqsanger.gz

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Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

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Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) remains one of the deadly cancer types. Comprehensively dissecting the molecular characterization and the heterogeneity of ESCC paves the way for developing more promising therapeutics.MethodsExpression profiles of multiple ESCC datasets were integrated. ATAC-seq and RNA-seq were combined to reveal the chromatin accessibility features. A prognosis-related subtype classifier (PrSC) was constructed, and its association with the tumor microenvironment (TME) and immunotherapy was assessed. The key gene signature was validated in clinical samples. Based on the TME heterogeneity of ESCC patients, potential subtype-specific therapeutic agents were screened.FindingsThe common differentially expressed genes (cDEGs) in ESCC were identified. Up-regulated genes (HEATR1, TIMELESS, DTL, GINS1, RUVBL1, and ECT2) were found highly important in ESCC cell survival. The expression alterations of PRIM2, HPGD, NELL2, and TFAP2B were associated with chromatin accessibility changes. PrSC was a robust scoring tool that was not only associated with the prognosis of ESCC patients, but also could reflect the TME heterogeneity. TNS1high fibroblasts were associated with immune exclusion. TG-101348 and Vinorelbine were identified as potential subtype-specific therapeutic agents. Besides, the application of PrSC into two immunotherapy cohorts indicated its potential value in assessing treatment response to immunotherapy.InterpretationOur study depicted the multi-dimensional characterization of ESCC, established a robust scoring tool for the prognosis assessment, highlighted the role of TNS1high fibroblasts in TME, and identified potential drugs for clinical use.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

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Project description:Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data ob-tained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I–IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial–mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC.

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