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Background <p>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.</p> Methods <p>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&#xa0;<i>in vitro</i>&#xa0;and&#xa0;a tail-vein experimental lung metastasis model.</p> Results <p>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&#xa0;<i>cis</i>- and&#xa0;<i>trans</i>-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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Yanan Pang,
  • Ye Gao,
  • Guobin Liu,
  • Jingxiang Zhao,
  • Han Lin,
  • Yilin Wang,
  • Lei Xin,
  • Wei Wang,
  • Yan Bian,
  • Yunfei Jiao,
  • Qiuxin Li,
  • Zengjun Li,
  • Zhaoshen Li,
  • He Huang,
  • Luowei Wang

摘要

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.