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Peer-reviewedCC BY-NC-NDMolecular cancer

Integrative multi-omics of esophageal squamous cell carcinoma reveals immune alterations and lactylation-driven mechanisms in metastatic progression.

  • Yanan Pang1,2
  • Ye Gao1,2
  • Guobin Liu3
  • Jingxiang Zhao4,5,6
  • Han Lin1,2
  • Yilin Wang7
  • Lei Xin1,2
  • Wei Wang1,2
  • Yan Bian1,2
  • Yunfei Jiao1,2
  • Qiuxin Li1,2
  • Zengjun Li8
3 more authors
  • Zhaoshen Li9,10
  • He Huang11,12,13,14
  • Luowei Wang15,16
16 affiliations
  1. 1Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
  2. 2National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  3. 3State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  4. 4School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  5. 5Lingang Laboratory, Shanghai, 200031, China.
  6. 6Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
  7. 7Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, 21218, USA.
  8. 8Endoscopy Department, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, 250117, Shandong Province, China. [email protected].
  9. 9Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. [email protected].
  10. 10National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China. [email protected].
  11. 11State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  12. 12School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  13. 13Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. [email protected].
  14. 14School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
  15. 15Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. [email protected].
  16. 16National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China. [email protected].
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Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is highly lethal owing to its early and aggressive metastasis, yet the underlying multi-layer molecular mechanisms remain incompletely understood, limiting therapeutic advances.Methods

We performed integrative multi-omics profiling (including genomics, transcriptomics, proteomics, and lactylome) on 99 matched primary tumor, metastatic lymph nodes, and normal esophagus tissue samples from 36 patients with metastatic ESCC. Molecular changes and cross-omics interactions associated with the metastatic cascades were characterized. Key findings were validated by immunohistochemistry and survival analysis in an independent cohort of 116 ESCC patients. Further functional and mechanistic studies were conducted using in vitro and a tail-vein experimental lung metastasis model.Results

Our analysis revealed pronounced disturbance in immune-related pathways closely associated with metastatic progression and poor prognosis. Intercellular adhesion molecule 1 (ICAM1) was identified as a critical factor of ESCC invasion and metastasis. Additionally, lysine-lactylated proteins were predominantly involved in cytoskeleton, focal adhesion and glycolysis pathways during ESCC metastasis. Integrative analysis revealed that the lactylome interacts with the genome and transcriptome through both cis- and trans-regulatory mechanisms, primarily in immune and metabolic pathways. Notably, lactylation of phosphoglycerate mutase 1 (PGAM1) at residue K251 enhances its interaction with actin gamma 1 and promotes metastatic phenotypes. ICAM1 and PGAM1 K251 lactylation represent two independent metastasis-associated mechanisms identified from the same multi-omics dataset.Conclusions

This integrative multi-omics characterization provides a comprehensive resource for metastatic ESCC research and identifies K251-lactylated PGAM1 as a candidate prognostic biomarker and mechanistic lead warranting further preclinical validation.

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Cite

BibTeXRIS
BibTeX
@article{pang2026integrative,
  title = {{Integrative multi-omics of esophageal squamous cell carcinoma reveals immune alterations and lactylation-driven mechanisms in metastatic progression.}},
  author = {Yanan Pang and Ye Gao and Guobin Liu and Jingxiang Zhao and Han Lin and Yilin Wang and Lei Xin and Wei Wang and Yan Bian and Yunfei Jiao and Qiuxin Li and Zengjun Li and Zhaoshen Li and He Huang and Luowei Wang},
  journal = {Molecular cancer},
  year = {2026},
  month = jul,
  doi = {10.1186/s12943-026-02755-x},
  url = {https://europepmc.org/article/MED/42928233},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrative multi-omics of esophageal squamous cell carcinoma reveals immune alterations and lactylation-driven mechanisms in metastatic progression.
AU  - Yanan Pang
AU  - Ye Gao
AU  - Guobin Liu
AU  - Jingxiang Zhao
AU  - Han Lin
AU  - Yilin Wang
AU  - Lei Xin
AU  - Wei Wang
AU  - Yan Bian
AU  - Yunfei Jiao
AU  - Qiuxin Li
AU  - Zengjun Li
AU  - Zhaoshen Li
AU  - He Huang
AU  - Luowei Wang
PY  - 2026
DA  - 2026/07/28
JO  - Molecular cancer
DO  - 10.1186/s12943-026-02755-x
UR  - https://europepmc.org/article/MED/42928233
AB  - Background  Esophageal squamous cell carcinoma (ESCC) is highly lethal owing to its early and aggressive metastasis, yet the underlying multi-layer molecular mechanisms remain incompletely understood, limiting therapeutic advances.Methods  We performed integrative multi-omics profiling (including genomics, transcriptomics, proteomics, and lactylome) on 99 matched primary tumor, metastatic lymph nodes, and normal esophagus tissue samples from 36 patients with metastatic ESCC. Molecular changes and cross-omics interactions associated with the metastatic cascades were characterized. Key findings were validated by immunohistochemistry and survival analysis in an independent cohort of 116 ESCC patients. Further functional and mechanistic studies were conducted using in vitro and a tail-vein experimental lung metastasis model.Results  Our analysis revealed pronounced disturbance in immune-related pathways closely associated with metastatic progression and poor prognosis. Intercellular adhesion molecule 1 (ICAM1) was identified as a critical factor of ESCC invasion and metastasis. Additionally, lysine-lactylated proteins were predominantly involved in cytoskeleton, focal adhesion and glycolysis pathways during ESCC metastasis. Integrative analysis revealed that the lactylome interacts with the genome and transcriptome through both cis- and trans-regulatory mechanisms, primarily in immune and metabolic pathways. Notably, lactylation of phosphoglycerate mutase 1 (PGAM1) at residue K251 enhances its interaction with actin gamma 1 and promotes metastatic phenotypes. ICAM1 and PGAM1 K251 lactylation represent two independent metastasis-associated mechanisms identified from the same multi-omics dataset.Conclusions  This integrative multi-omics characterization provides a comprehensive resource for metastatic ESCC research and identifies K251-lactylated PGAM1 as a candidate prognostic biomarker and mechanistic lead warranting further preclinical validation.
SN  - 1476-4598
ER  -