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

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^*

^*Corresponding author for this work

University of Texas MD Anderson Cancer Center
University of Pennsylvania
Vanderbilt University

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

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.

Original language	English
Pages (from-to)	905-924.e6
Journal	Cancer Cell
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2025.03.004
State	Published - 12 May 2025
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

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10.1016/j.ccell.2025.03.004

Cite this

Liu, Y., Sinjab, A., Min, J., Han, G., Paradiso, F., Zhang, Y., Wang, R., Pei, G., Dai, Y., Liu, Y., Cho, K. S., Dai, E., Basi, A., Burks, J. K., Rajapakshe, K. I., Chu, Y., Jiang, J., Zhang, D., Yan, X., ... Wang, L. (2025). Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics. Cancer Cell, 43(5), 905-924.e6. https://doi.org/10.1016/j.ccell.2025.03.004

@article{e929e8bda76f4b09b9cbd8a5ad85ef71,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = may,

day = "12",

doi = "10.1016/j.ccell.2025.03.004",

language = "英语",

volume = "43",

pages = "905--924.e6",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Liu, Y, Sinjab, A, Min, J, Han, G, Paradiso, F, Zhang, Y, Wang, R, Pei, G, Dai, Y, Liu, Y, Cho, KS, Dai, E, Basi, A, Burks, JK, Rajapakshe, KI, Chu, Y, Jiang, J, Zhang, D, Yan, X, Guerrero, PA, Serrano, A, Li, M, Hwang, TH, Futreal, A, Ajani, JA, Solis Soto, LM, Jazaeri, AA, Kadara, H, Maitra, A & Wang, L 2025, 'Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics', Cancer Cell, vol. 43, no. 5, pp. 905-924.e6. https://doi.org/10.1016/j.ccell.2025.03.004

TY - JOUR

T1 - Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics

AU - Liu, Yunhe

AU - Sinjab, Ansam

AU - Min, Jimin

AU - Han, Guangchun

AU - Paradiso, Francesca

AU - Zhang, Yuanyuan

AU - Wang, Ruiping

AU - Pei, Guangsheng

AU - Dai, Yibo

AU - Liu, Yang

AU - Cho, Kyung Serk

AU - Dai, Enyu

AU - Basi, Akshay

AU - Burks, Jared K.

AU - Rajapakshe, Kimal I.

AU - Chu, Yanshuo

AU - Jiang, Jiahui

AU - Zhang, Daiwei

AU - Yan, Xinmiao

AU - Guerrero, Paola A.

AU - Serrano, Alejandra

AU - Li, Mingyao

AU - Hwang, Tae Hyun

AU - Futreal, Andrew

AU - Ajani, Jaffer A.

AU - Solis Soto, Luisa M.

AU - Jazaeri, Amir A.

AU - Kadara, Humam

AU - Maitra, Anirban

AU - Wang, Linghua

PY - 2025/5/12

Y1 - 2025/5/12

N2 - 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.

AB - 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.

KW - cancer-associated fibroblast

KW - cell-cell communication

KW - cellular neighborhood

KW - lymphoid aggregate

KW - pan-cancer

KW - spatial multi-omics

KW - spatial transcriptomics

KW - tertiary lymphoid structure

KW - tumor associated macrophage

KW - tumor microenvironment

UR - https://www.scopus.com/pages/publications/105001415859

U2 - 10.1016/j.ccell.2025.03.004

DO - 10.1016/j.ccell.2025.03.004

M3 - 文章

C2 - 40154487

AN - SCOPUS:105001415859

SN - 1535-6108

VL - 43

SP - 905-924.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

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Keywords

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