The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas

作者：Bonan Chen, Wai Nok Chan, Fuda Xie, Chun Wai Mui, Xiaoli Liu, Alvin H.K. Cheung, Raymond Wai Ming Lung, Chit Chow, Zhenhua Zhang, Canbin Fang, Peiyao Yu, Shihua Shi, Shikun Zhou, Guoming Chen, Zhangding Wang, Shouyu Wang, Xiaofan Ding, Bing Huang, Liang Li, Yujuan Dong, Chi Chun Wong, William Ka Kei Wu, Alfred S.L. Cheng, Nathalie Wong, Jun Yu, Kwok Wai Lo, Gary M. Tse, Wei Kang, Ka‐Fai To · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1516 · 被引用次数：70 · 研究领域：Single-cell and spatial transcriptomics、Cancer Cells and Metastasis、Immune cells in cancer

BACKGROUND: Cancer-associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro-tumourigenic or anti-tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single-cell pan-cancer scale has yet to be established. METHODS: We employed a comprehensive single-cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single-Cell Regulatory Network Inference and Clustering and single-cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix-producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments. RESULTS: In our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammato...