1. Academic Validation
  2. Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

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

  • EBioMedicine. 2021 Aug;70:103510. doi: 10.1016/j.ebiom.2021.103510.
Yin Li 1 Fengkai Xu 1 Fanghua Chen 2 Yiwei Chen 1 Di Ge 1 Shu Zhang 3 Chunlai Lu 4
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
  • 3 Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 4 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
Abstract

Background: Esophageal 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.

Methods: Expression 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.

Findings: The 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.

Interpretation: Our 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.

Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Keywords

ATAC-seq; Drug repurposing; Esophageal squamous cell carcinoma; Molecular classification; RNA-seq; Tumor stroma.

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