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  3. The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional atlas

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

  • Clin Transl Med. 2023 Dec;13(12):e1516. doi: 10.1002/ctm2.1516.
Bonan Chen 1 2 3,  Wai Nok Chan 1 2 3,  Fuda Xie 1 2 3,  Chun Wai Mui 1 2 3,  Xiaoli Liu 1 2 3,  Alvin H K Cheung 1,  Raymond W M Lung 1,  Chit Chow 1,  Zhenhua Zhang 4,  Canbin Fang 1,  Peiyao Yu 5,  Shihua Shi 6 7,  Shikun Zhou 8,  Guoming Chen 9,  Zhangding Wang 10,  Shouyu Wang 11,  Xiaofan Ding 12,  Bing Huang 13,  Li Liang 5,  Yujuan Dong 14,  Chi Chun Wong 2,  William K K Wu 15,  Alfred S L Cheng 16,  Nathalie Wong 14,  Jun Yu 2 17,  Kwok Wai Lo 1,  Gary M K Tse 1,  Wei Kang 1 2 3,  Ka Fai To 1 2 3
Affiliations

Affiliations

  • 1 Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
  • 2 Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
  • 3 CUHK-Shenzhen Research Institute, Shenzhen, China.
  • 4 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
  • 5 Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangzhou, China.
  • 6 Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 7 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 8 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, China.
  • 9 School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 10 Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 11 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 12 Faculty of Health Sciences, University of Macau, Macao, China.
  • 13 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 14 Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
  • 15 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
  • 16 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 17 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
PMID: 38148640 DOI: 10.1002/ctm2.1516
Abstract

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), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several Cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity.

Conclusions: Collectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of Cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for Cancer treatment.

Keywords

cancer-associated fibroblast; molecular classification; pan-cancer; single-cell transcriptional atlas.

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