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

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 () and Xiao Xu ()
Additional contact information
Sunbin Ling: Hangzhou Medical College
Jiongjie Yu: Zhejiang University
Qifan Zhan: Zhejiang University
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
Shuqi Cai: Zhejiang University
Wei Zhou: Zhejiang University
Qingyang Que: Zhejiang University
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
Jinzhen Cai: The Affiliated Hospital of Qingdao University
Liming Wang: Dalian Medical University
Shusen Zheng: NHC Key Laboratory of Combined Multi-organ Transplantation
Xiao Xu: Hangzhou Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59745-8

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