Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved..
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.
| Errataetall: |
CommentIn: EBioMedicine. 2021 Sep;71:103545. - PMID 34419929 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:70 |
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| Enthalten in: |
EBioMedicine - 70(2021) vom: 30. Aug., Seite 103510 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Yin [VerfasserIn] |
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| Links: |
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| Themen: |
ATAC-seq |
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| Anmerkungen: |
Date Completed 12.01.2022 Date Revised 28.01.2022 published: Print-Electronic CommentIn: EBioMedicine. 2021 Sep;71:103545. - PMID 34419929 Citation Status MEDLINE |
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| doi: |
10.1016/j.ebiom.2021.103510 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a CommentIn: EBioMedicine. 2021 Sep;71:103545. - PMID 34419929 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATAC-seq | |
| 650 | 4 | |a Drug repurposing | |
| 650 | 4 | |a Esophageal squamous cell carcinoma | |
| 650 | 4 | |a Molecular classification | |
| 650 | 4 | |a RNA-seq | |
| 650 | 4 | |a Tumor stroma | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a Vinorelbine |2 NLM | |
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| 700 | 1 | |a Chen, Fanghua |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Di |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Chunlai |e verfasserin |4 aut | |
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