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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月12日

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  • 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,
  • Jianan Xiang,
  • Shengjun Xu,
  • Jimin Liu,
  • Xiaojun Peng,
  • Nan Wang,
  • Weixin Wang,
  • Haiyang Xie,
  • Jinzhen Cai,
  • Liming Wang,
  • Shusen Zheng,
  • Xiao Xu

摘要

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.