Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
EBioMedicine. 2021 Aug;70:103510. doi: 10.1016/j.ebiom.2021.103510. Epub 2021 Aug 5.
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.
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.
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. TNS1 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.
Our study depicted the multi-dimensional characterization of ESCC, established a robust scoring tool for the prognosis assessment, highlighted the role of TNS1 fibroblasts in TME, and identified potential drugs for clinical use.
A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
食管鳞状细胞癌（ESCC）仍然是致命的癌症类型之一。全面剖析 ESCC 的分子特征和异质性为开发更有前途的治疗方法铺平了道路。
整合了多个 ESCC 数据集的表达谱。结合 ATAC-seq 和 RNA-seq 揭示染色质可及性特征。构建了与预后相关的亚型分类器（PrSC），并评估了其与肿瘤微环境（TME）和免疫治疗的关联。在临床样本中验证了关键基因特征。根据 ESCC 患者的 TME 异质性，筛选潜在的亚型特异性治疗药物。
确定了 ESCC 中的常见差异表达基因（cDEGs）。上调基因（HEATR1、TIMELESS、DTL、GINS1、RUVBL1 和 ECT2）在 ESCC 细胞存活中起着至关重要的作用。PRIM2、HPGD、NELL2 和 TFAP2B 的表达改变与染色质可及性变化有关。PrSC 是一种强大的评分工具，不仅与 ESCC 患者的预后相关，而且可以反映 TME 的异质性。TNS1 成纤维细胞与免疫排斥有关。TG-101348 和长春瑞滨被确定为潜在的亚型特异性治疗药物。此外，将 PrSC 应用于两个免疫治疗队列表明其在评估免疫治疗反应方面具有潜在价值。
我们的研究描绘了 ESCC 的多维特征，建立了一种用于预后评估的强大评分工具，强调了 TNS1 成纤维细胞在 TME 中的作用，并确定了潜在的临床用药。
对本研究做出贡献的资助机构的完整列表可在致谢部分找到。
Zotero 插件
