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Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria

Author

Listed:
  • Sunbin Ling

    (Hangzhou Medical College
    Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Jiongjie Yu

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Qifan Zhan

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Mingwei Gao

    (Dalian Medical University)

  • Peng Liu

    (The Affiliated Hospital of Qingdao University)

  • Yongfeng Wu

    (Hangzhou First People’s Hospital)

  • Lincheng Zhang

    (Tsinghua University)

  • Qiaonan Shan

    (Zhejiang University School of Medicine)

  • Huan Liu

    (The Affiliated Hospital of Qingdao University)

  • Jiapei Wang

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Shuqi Cai

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Wei Zhou

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Qingyang Que

    (Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Shuo Wang

    (Zhejiang Shuren University School of Medicine)

  • Jiachen Hong

    (Hangzhou First People’s Hospital)

  • Jianan Xiang

    (Hangzhou First People’s Hospital)

  • Shengjun Xu

    (Hangzhou First People’s Hospital)

  • Jimin Liu

    (Mt Sinai Hospital)

  • Xiaojun Peng

    (Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province)

  • Nan Wang

    (Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province)

  • Weixin Wang

    (Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province)

  • Haiyang Xie

    (NHC Key Laboratory of Combined Multi-organ Transplantation
    Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences (2019RU019))

  • Jinzhen Cai

    (The Affiliated Hospital of Qingdao University)

  • Liming Wang

    (Dalian Medical University)

  • Shusen Zheng

    (NHC Key Laboratory of Combined Multi-organ Transplantation
    Zhejiang University School of Medicine
    Zhejiang Shuren University School of Medicine
    Chinese Academy of Medical Sciences (2019RU019))

  • Xiao Xu

    (Hangzhou Medical College
    Zhejiang University
    NHC Key Laboratory of Combined Multi-organ Transplantation
    Hangzhou First People’s Hospital)

Abstract

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria, liver transplantation (LT) is an effective therapy. This study aims to define the survival-related molecular biological features helping precisely identifying the patients with HCC beyond the Milan criteria who have acceptable outcomes. In the derivation cohort, integrated analyses of tumor tissues are conducted using RNA sequencing (RNA-seq), proteomic landscape, and transposase-accessible chromatin sequencing (ATAC-seq). Based on transcriptomics, three subgroups that significantly differ in overall survival were identified in the derivation cohort, and these findings are validated in an independent cohort. In-depth bioinformatics analysis using RNA-seq and proteomics reveals that the promotion of cancer stemness by cancer-associated fibroblasts (CAFs) can be responsible for the negative biological characteristics observed in high-risk HCC patients. The ATAC-seq identifies key factors regulating transcription, which may bridge CAF infiltration and stemness. Finally, we demonstrate that the CAF-derived CXCL12 sustains the stemness of HCC cells by promoting XRCC5 through CXCR4.

Suggested Citation

  • Sunbin Ling & Jiongjie Yu & Qifan Zhan & Mingwei Gao & Peng Liu & Yongfeng Wu & Lincheng Zhang & Qiaonan Shan & Huan Liu & Jiapei Wang & Shuqi Cai & Wei Zhou & Qingyang Que & Shuo Wang & Jiachen Hong , 2025. "Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59745-8
    DOI: 10.1038/s41467-025-59745-8
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