Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics

Yunhe Liu; Ansam Sinjab; Jimin Min; Guangchun Han; Francesca Paradiso; Yuanyuan Zhang; Ruiping Wang; Guangsheng Pei; Yibo Dai; Yang Liu; Kyung Serk Cho; Enyu Dai; Akshay Basi; Jared K Burks; Kimal I Rajapakshe; Yanshuo Chu; Jiahui Jiang; Daiwei Zhang; Xinmiao Yan; Paola A Guerrero; Alejandra Serrano; Mingyao Li; Tae Hyun Hwang; Andrew Futreal; Jaffer A Ajani; Luisa M Solis Soto; Amir A Jazaeri; Humam Kadara; Anirban Maitra; Linghua Wang

doi:10.1016/j.ccell.2025.03.004

Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics

Cancer Cell. 2025 May 12;43(5):905-924.e6. doi: 10.1016/j.ccell.2025.03.004. Epub 2025 Mar 27.

Authors

Yunhe Liu¹, Ansam Sinjab², Jimin Min³, Guangchun Han¹, Francesca Paradiso², Yuanyuan Zhang¹, Ruiping Wang¹, Guangsheng Pei¹, Yibo Dai⁴, Yang Liu¹, Kyung Serk Cho¹, Enyu Dai¹, Akshay Basi⁵, Jared K Burks⁵, Kimal I Rajapakshe⁶, Yanshuo Chu¹, Jiahui Jiang¹, Daiwei Zhang⁷, Xinmiao Yan¹, Paola A Guerrero², Alejandra Serrano², Mingyao Li⁷, Tae Hyun Hwang⁸, Andrew Futreal¹, Jaffer A Ajani⁹, Luisa M Solis Soto², Amir A Jazaeri¹⁰, Humam Kadara¹¹, Anirban Maitra¹², Linghua Wang¹³

Affiliations

¹ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA.
⁵ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁹ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA. Electronic address: hkadara@mdanderson.org.
¹² Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: amaitra@mdanderson.org.
¹³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lwang22@mdanderson.org.

PMID: 40154487
PMCID: PMC12074878 (available on 2026-05-12)
DOI: 10.1016/j.ccell.2025.03.004

Abstract

Cancer-associated fibroblasts (CAFs) are a multifaceted cell population essential for shaping the tumor microenvironment (TME) and influencing therapy responses. Characterizing the spatial organization and interactions of CAFs within complex tissue environments provides critical insights into tumor biology and immunobiology. In this study, through integrative analyses of over 14 million cells from 10 cancer types across 7 spatial transcriptomics and proteomics platforms, we discover, validate, and characterize four distinct spatial CAF subtypes. These subtypes are conserved across cancer types and independent of spatial omics platforms. Notably, they exhibit distinct spatial organizational patterns, neighboring cell compositions, interaction networks, and transcriptomic profiles. Their abundance and composition vary across tissues, shaping TME characteristics, such as levels, distribution, and state composition of tumor-infiltrating immune cells, tumor immune phenotypes, and patient survival. This study enriches our understanding of CAF spatial heterogeneity in cancer and paves the way for novel approaches to target and modulate CAFs.

Keywords: cancer-associated fibroblast; cell-cell communication; cellular neighborhood; lymphoid aggregate; pan-cancer; spatial multi-omics; spatial transcriptomics; tertiary lymphoid structure; tumor associated macrophage; tumor microenvironment.

MeSH terms

Cancer-Associated Fibroblasts* / immunology
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Multiomics
Neoplasms* / genetics
Neoplasms* / immunology
Neoplasms* / metabolism
Neoplasms* / pathology
Proteomics* / methods
Single-Cell Analysis* / methods
Transcriptome
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology

Abstract

MeSH terms

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