Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59745-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850154622918852608 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Sunbin Ling |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c15337716d3646f59b2f018a18a87f49 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c15337716d3646f59b2f018a18a87f492025-08-20T02:25:16ZengNature PortfolioNature Communications2041-17232025-05-0116111310.1038/s41467-025-59745-8Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteriaSunbin Ling0Jiongjie Yu1Qifan Zhan2Mingwei Gao3Peng Liu4Yongfeng Wu5Lincheng Zhang6Qiaonan Shan7Huan Liu8Jiapei Wang9Shuqi Cai10Wei Zhou11Qingyang Que12Shuo Wang13Jiachen Hong14Jianan Xiang15Shengjun Xu16Jimin Liu17Xiaojun Peng18Nan Wang19Weixin Wang20Haiyang Xie21Jinzhen Cai22Liming Wang23Shusen Zheng24Xiao Xu25Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), School of Clinical Medicine, Hangzhou Medical CollegeInstitute of Translational Medicine, Zhejiang UniversityInstitute of Translational Medicine, Zhejiang UniversityEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical UniversityOrgan Transplantation Center, The Affiliated Hospital of Qingdao UniversityKey Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People’s HospitalSchool of Clinical Medicine, Tsinghua UniversityDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of MedicineOrgan Transplantation Center, The Affiliated Hospital of Qingdao UniversityInstitute of Translational Medicine, Zhejiang UniversityInstitute of Translational Medicine, Zhejiang UniversityInstitute of Translational Medicine, Zhejiang UniversityInstitute of Translational Medicine, Zhejiang UniversityShulan (Hangzhou) Hospital, Zhejiang Shuren University School of MedicineKey Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People’s HospitalKey Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People’s HospitalKey Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People’s HospitalDepartment of Pathology and Laboratory Medicine, Mt Sinai HospitalKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang ProvinceKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang ProvinceKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang ProvinceNHC Key Laboratory of Combined Multi-organ TransplantationOrgan Transplantation Center, The Affiliated Hospital of Qingdao UniversityEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical UniversityNHC Key Laboratory of Combined Multi-organ TransplantationDepartment of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), School of Clinical Medicine, Hangzhou Medical CollegeAbstract 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.https://doi.org/10.1038/s41467-025-59745-8 |
| spellingShingle | 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 Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria Nature Communications |
| title | Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria |
| title_full | Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria |
| title_fullStr | Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria |
| title_full_unstemmed | Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria |
| title_short | Multi-omic analysis reveals a CAF-stemness-governed classification in HCC liver transplant recipients beyond the Milan criteria |
| title_sort | multi omic analysis reveals a caf stemness governed classification in hcc liver transplant recipients beyond the milan criteria |
| url | https://doi.org/10.1038/s41467-025-59745-8 |
| work_keys_str_mv | AT sunbinling multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jiongjieyu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT qifanzhan multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT mingweigao multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT pengliu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT yongfengwu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT linchengzhang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT qiaonanshan multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT huanliu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jiapeiwang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT shuqicai multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT weizhou multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT qingyangque multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT shuowang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jiachenhong multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jiananxiang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT shengjunxu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jiminliu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT xiaojunpeng multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT nanwang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT weixinwang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT haiyangxie multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT jinzhencai multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT limingwang multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT shusenzheng multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria AT xiaoxu multiomicanalysisrevealsacafstemnessgovernedclassificationinhcclivertransplantrecipientsbeyondthemilancriteria |