Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma.

IF 13 1区生物学 Q1 CELL BIOLOGY

Cell Discovery Pub Date : 2025-01-28 DOI:10.1038/s41421-024-00747-z

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

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引用次数: 0

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.

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来源期刊

Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

24.20

自引率

0.60%

发文量

120

审稿时长

20 weeks

期刊介绍： Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.