Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma
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 biologic...
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| creator | Cheng, Yifei Chen, Xiaofang Feng, Li Yang, Zhicheng Xiao, Liyun Xiang, Bin Wang, Xiaodong Liu, Dongbin Lin, Penghui Shi, Jieyi Song, Guohe Qian, Wulei Zhang, Boan Xu, Yanan Gao, Zheng Chen, Lv Wu, Yingcheng Ma, Jiaqiang Lin, Youpei Zhao, Haichao Peng, Lihua Mao, Xuebin Liu, Yang Hou, Hao Yang, Mingyu Ji, Yuan Wang, Xiaoying Zhou, Jian Xu, Xun Liu, Xiyang Wei, Wu Zhang, Xiaoming Gao, Qiang Zhou, Hu Sun, Yidi Wu, Kui Fan, Jia |
| description | 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. |
| doi_str_mv | 10.1038/s41421-024-00747-z |
| format | Article |
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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.</description><identifier>ISSN: 2056-5968</identifier><identifier>EISSN: 2056-5968</identifier><identifier>DOI: 10.1038/s41421-024-00747-z</identifier><identifier>PMID: 39870619</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>631/250/580 ; 631/67/327 ; Biomedical and Life Sciences ; Cell Biology ; Cell Culture ; Cell Cycle Analysis ; Cell Physiology ; Life Sciences ; Stem Cells</subject><ispartof>Cell discovery, 2025-01, Vol.11 (1), p.1-24, Article 1</ispartof><rights>The Author(s) 2025</rights><rights>2025. 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| subjects | 631/250/580 631/67/327 Biomedical and Life Sciences Cell Biology Cell Culture Cell Cycle Analysis Cell Physiology Life Sciences Stem Cells |
| title | Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma |
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