Single-cell transcriptomic analysis deciphers key transitional signatures associated with oncogenic evolution in human intramucosal oesophageal squamous cell carcinoma

Sep 24, 2026

Single-cell transcriptomic analysis is used to address the need for early diagnosis and intervention in oesophageal squamous cell carcinoma (ESCC), where effective therapies remain limited and prognosis is poor. The study builds a cellular atlas of human intramucosal ESCC using paired intramucosal tumor tissues, para-ESCC tissues, and peripheral blood mononuclear cells for scRNA-seq. Across 164,715 cells, epithelial evolutionary trajectories and immune exhaustion signals are characterized, and ligand–receptor interactions are linked to CAF activation and early tumor microenvironment remodeling. Identified genes and malignant subclusters serve as poor-prognosis biomarkers and potential targets.

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Abstract

Background and aims

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Introduction

DOI: 10.1002/ctm2.1203 RESEARCH ARTICLE Single-cell transcriptomic analysis deciphers key transitional signatures associated with oncogenic evolution in human intramucosal oesophageal squamous cell carcinoma Xin-Yang Liu1,2 Yuan-Yuan Ruan3 Meng-Jiang He1,2 Yi-Qun Zhang1,2 Yan-Bo Liu1,2 Jia-Cheng Xu1,2 Yi-Fei Zhang1,2 Yi Zhao4 Lin-Feng Wu1,2 Jian-Wei Hu1,2 Zhen Zhang1,2 Tian-Yin Chen1,2 Xiao-Yue Xu1,2 Jing-Wei Zhang5 Ping-Hong Zhou1,2 1 Department of Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Endoscopy, Shanghai Collaborative Innovation Center, Shanghai, China 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China 4 GobioX BioTech, Shanghai, China 5 Department of Genetic Engineering State Key Laboratory, School of Life Sciences, Fudan University, Shanghai, China Correspondence Yi-Qun Zhang, Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China. Email: [zhang.yiqun@zs-hospital.sh.cn](zhang.yiqun@zs-hospital.sh.cn) [Ping-Hong Zhou](Ping-Hong Zhou), [Endoscopy Center and](Endoscopy Center and)[ ](Endoscopy Center and)Endoscopy Research Institute, Zhongshan Hospital, Fudan University; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China. Email: [zhou.pinghong@zs-hospital.sh.cn](zhou.pinghong@zs-hospital.sh.cn) [Drs. Xin-Yang Liu](Drs. Xin-Yang Liu), [Yan-Bo Liu and](Yan-Bo Liu and) [Jia-Cheng Xu shared co-first authorship.](Jia-Cheng Xu shared co-first authorship.) Funding information Shanghai Municipal Health Commission Collaborative Innovation Cluster Project, Grant/Award Number: 2019CXJQ02; National Natural Science Foundation of China, Grant/Award Numbers: 82003074, 82172787; Chen Guang Program of Abstract Background and aims: The early diagnosis and intervention of oesophageal squamous cell carcinoma (ESCC) are particularly important because of the lack of effective therapies and poor prognosis. Comprehensive research on early ESCC at the single-cell level is rare due to the need for fresh and high-quality specimens obtained from ESD. This study aims to systematically describe the cellular atlas of human intramucosal ESCC. Methods: Five paired samples of intramucosal ESCC, para-ESCC oesophageal tissues from endoscopically resected specimens and peripheral blood mononuclear cells were adopted for scRNA-seq analysis. Computational pipelinescMetabolism was applied to quantify the metabolic diversity of single cells. Results: A total of 164 715 cells were profiled. Epithelial cells exhibited high intra-tumoural heterogeneity and two evolutionary trajectories during ESCC tumorigenesis initiated from proliferative cells, and then through an intermediate state, to two different terminal states of normally differentiated epithelial cells or malignant cells, respectively. The abundance of CD8+ TEXs, Tregs and PD1+ CD4+T cells suggested an exhausted and suppressive immune microenvironment. Several genes in immune cells, such as CXCL13, CXCR5 and PADI4, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. Clin. Transl. Med. 2023;13:e1203 . [https://doi.org/10.1002/ctm2.1203](https://doi.org/10.1002/ctm2.1203) [wileyonlinelibrary.com/journal/ctm2](wileyonlinelibrary.com/journal/ctm2) 1 of 20 LIU et al. Shanghai Municipal Education Committee, Grant/Award Number: 18CG07; Shanghai ‘Rising Stars of Medical Talent’Youth Development Program, Grant/Award Number: SHWJRS(2021)-99 were identified as new

FAQs

What is the study’s main goal in ESCC research?

To systematically describe the cellular atlas of human intramucosal ESCC and identify key transitional signatures linked to oncogenic evolution for early diagnosis and intervention.

How were samples and sequencing data generated and analyzed?

Five paired samples from intramucosal ESCC, para-ESCC tissues, and peripheral blood mononuclear cells were used for scRNA-seq, followed by computational pipelines (including cMetabolism) to quantify cellular diversity and related programs.

What did the study find about epithelial evolution and immune microenvironment?

Epithelial cells showed high intra-tumoural heterogeneity with two evolutionary trajectories, and immune signals including CD8+ TEXs, Tregs, and PD1+ CD4+ T cells indicated an exhausted and suppressive immune microenvironment.

Which interaction pathway and biomarker candidates were identified?

Ligand–receptor interaction analysis highlighted malignant-cell interactions with CAFs via the MDK–NCL pathway, supported by proliferation assays and IHC; several immune-related genes (e.g., CXCL13, CXCR5, PADI4) and an early metastasis/angiogenesis-associated malignant subcluster were proposed as poor-prognosis biomarkers.

Sep 24, 2026

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