Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma
Abstract Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00747-z |
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| author | Yifei Cheng Xiaofang Chen Li Feng Zhicheng Yang Liyun Xiao Bin Xiang Xiaodong Wang Dongbin Liu Penghui Lin Jieyi Shi Guohe Song Wulei Qian Boan Zhang Yanan Xu Zheng Gao Lv Chen Yingcheng Wu Jiaqiang Ma Youpei Lin Haichao Zhao Lihua Peng Xuebin Mao Yang Liu Hao Hou Mingyu Yang Yuan Ji Xiaoying Wang Jian Zhou Xun Xu Xiyang Liu Wu Wei Xiaoming Zhang Qiang Gao Hu Zhou Yidi Sun Kui Wu Jia Fan |
| author_facet | Yifei Cheng Xiaofang Chen Li Feng Zhicheng Yang Liyun Xiao Bin Xiang Xiaodong Wang Dongbin Liu Penghui Lin Jieyi Shi Guohe Song Wulei Qian Boan Zhang Yanan Xu Zheng Gao Lv Chen Yingcheng Wu Jiaqiang Ma Youpei Lin Haichao Zhao Lihua Peng Xuebin Mao Yang Liu Hao Hou Mingyu Yang Yuan Ji Xiaoying Wang Jian Zhou Xun Xu Xiyang Liu Wu Wei Xiaoming Zhang Qiang Gao Hu Zhou Yidi Sun Kui Wu Jia Fan |
| author_sort | Yifei Cheng |
| collection | DOAJ |
| description | Abstract Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different biological functions and extracellular matrix compositions. Using paired single-cell RNA and epigenomic sequencing with Stereo-seq, we revealed two fibroblast subsets CAF-FAP and CAF-C7, whose spatial enrichment strongly correlated with the two stromal archetypes and opposing patient prognosis. We discovered two functional units, one is the intratumor inflammatory hub featured by CAF-FAP plus CD8_PDCD1 proximity and the other is the marginal wound-healing hub with CAF-C7 plus Macrophage_SPP1 co-localization. Inhibiting CAF-FAP combined with anti-PD-1 in orthotopic HCC models led to improved tumor regression than either monotherapy. Collectively, our findings suggest stroma-targeted strategies for HCC based on defined stromal archetypes, raising the concept that CAFs change their transcriptional program and intercellular crosstalk according to the spatial context. |
| format | Article |
| id | doaj-art-747d0c7a8f754074a7a6cf6a4dd18adc |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-747d0c7a8f754074a7a6cf6a4dd18adc2025-02-02T12:08:26ZengNature Publishing GroupCell Discovery2056-59682025-01-0111112410.1038/s41421-024-00747-zStromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinomaYifei Cheng0Xiaofang Chen1Li Feng2Zhicheng Yang3Liyun Xiao4Bin Xiang5Xiaodong Wang6Dongbin Liu7Penghui Lin8Jieyi Shi9Guohe Song10Wulei Qian11Boan Zhang12Yanan Xu13Zheng Gao14Lv Chen15Yingcheng Wu16Jiaqiang Ma17Youpei Lin18Haichao Zhao19Lihua Peng20Xuebin Mao21Yang Liu22Hao Hou23Mingyu Yang24Yuan Ji25Xiaoying Wang26Jian Zhou27Xun Xu28Xiyang Liu29Wu Wei30Xiaoming Zhang31Qiang Gao32Hu Zhou33Yidi Sun34Kui Wu35Jia Fan36Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchInstitute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of SciencesDepartment of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchKey Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of SciencesSchool of Computer Science and Technology, Xidian UniversityHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversitySchool of Computer Science and Technology, Xidian UniversitySchool of Computer Science and Technology, Xidian UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchBGI ResearchHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchDepartment of Pathology, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityGuangdong Provincial Key Laboratory of Genome Read and Write, BGI ResearchSchool of Computer Science and Technology, Xidian UniversityKey Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of SciencesThe Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of SciencesDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesInstitute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of SciencesHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI ResearchDepartment of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityAbstract Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different biological functions and extracellular matrix compositions. Using paired single-cell RNA and epigenomic sequencing with Stereo-seq, we revealed two fibroblast subsets CAF-FAP and CAF-C7, whose spatial enrichment strongly correlated with the two stromal archetypes and opposing patient prognosis. We discovered two functional units, one is the intratumor inflammatory hub featured by CAF-FAP plus CD8_PDCD1 proximity and the other is the marginal wound-healing hub with CAF-C7 plus Macrophage_SPP1 co-localization. Inhibiting CAF-FAP combined with anti-PD-1 in orthotopic HCC models led to improved tumor regression than either monotherapy. Collectively, our findings suggest stroma-targeted strategies for HCC based on defined stromal archetypes, raising the concept that CAFs change their transcriptional program and intercellular crosstalk according to the spatial context.https://doi.org/10.1038/s41421-024-00747-z |
| spellingShingle | Yifei Cheng Xiaofang Chen Li Feng Zhicheng Yang Liyun Xiao Bin Xiang Xiaodong Wang Dongbin Liu Penghui Lin Jieyi Shi Guohe Song Wulei Qian Boan Zhang Yanan Xu Zheng Gao Lv Chen Yingcheng Wu Jiaqiang Ma Youpei Lin Haichao Zhao Lihua Peng Xuebin Mao Yang Liu Hao Hou Mingyu Yang Yuan Ji Xiaoying Wang Jian Zhou Xun Xu Xiyang Liu Wu Wei Xiaoming Zhang Qiang Gao Hu Zhou Yidi Sun Kui Wu Jia Fan Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma Cell Discovery |
| title | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| title_full | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| title_fullStr | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| title_full_unstemmed | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| title_short | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| title_sort | stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41421-024-00747-z |
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