Pan-cancer Single-cell Analysis Reveals the Heterogeneity and Plasticity of Cancer-associated Fibroblasts in the Tumor Microenvironment

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 5

PMID 36333338

Authors

Han Luo

Xuyang Xia

Li-Bin Huang

Hyunsu An

Minyuan Cao

Gyeong Dae Kim

Hai-Ning Chen

Wei-Han Zhang

Yang Shu

Xiangyu Kong

Zhixiang Ren

Pei-Heng Li

Yang Liu

Huairong Tang

Ronghao Sun

Chao Li

Bing Bai

Weiguo Jia

Yi Liu

Wei Zhang

Li Yang

Yong Peng

Lunzhi Dai

Hongbo Hu

Yong Jiang

Yiguo Hu

Jingqiang Zhu

Hong Jiang

Zhihui Li

Carlos Caulin

Jihwan Park

Heng Xu

Affiliations

Soon will be listed here.

Abstract

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1 tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .

Citing Articles

Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis.

Leung M, Swanton C, McGranahan N Nat Rev Genet. 2025; .

PMID: 40065153 DOI: 10.1038/s41576-025-00825-2.

Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors.

Patte C, Pommier R, Ferrari A, Chung F, Ouzounova M, Moulle P Nat Commun. 2025; 16(1):2197.

PMID: 40038310 PMC: 11880452. DOI: 10.1038/s41467-025-57305-8.

Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response.

Song J, Wei R, Liu C, Zhao Z, Liu X, Wang Y Nat Commun. 2025; 16(1):2175.

PMID: 40038297 PMC: 11880398. DOI: 10.1038/s41467-025-57465-7.

Single cell immunoprofile of synovial fluid in rheumatoid arthritis with TNF/JAK inhibitor treatment.

Xia X, He C, Xue Z, Wang Y, Qin Y, Ren Z Nat Commun. 2025; 16(1):2152.

PMID: 40038288 PMC: 11880340. DOI: 10.1038/s41467-025-57361-0.

Differential cellular origins of the extracellular matrix of tumor and normal tissues according to colorectal cancer subtypes.

Lee H, Park S, Lee J, Chang S, Oh S, Mun S Br J Cancer. 2025; .

PMID: 40032993 DOI: 10.1038/s41416-025-02964-z.

References

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

Barkal A, Brewer R, Markovic M, Kowarsky M, Barkal S, Zaro B . CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 2019; 572(7769):392-396. PMC: 6697206. DOI: 10.1038/s41586-019-1456-0. View

McAndrews K, Chen Y, Darpolor J, Zheng X, Yang S, Carstens J . Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer. Cancer Discov. 2022; 12(6):1580-1597. PMC: 9399904. DOI: 10.1158/2159-8290.CD-20-1484. View

Rauch A, Mandrup S . Transcriptional networks controlling stromal cell differentiation. Nat Rev Mol Cell Biol. 2021; 22(7):465-482. DOI: 10.1038/s41580-021-00357-7. View

Fearon D . The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014; 2(3):187-93. DOI: 10.1158/2326-6066.CIR-14-0002. View

Wang Y, Jiang H, Pan J, Huang X, Wang Y, Huang H . Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury. J Am Soc Nephrol. 2017; 28(7):2053-2067. PMC: 5491278. DOI: 10.1681/ASN.2016050573. View

Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y . Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun. 2020; 11(1):5077. PMC: 7545162. DOI: 10.1038/s41467-020-18916-5. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Chen S, Zhu G, Yang Y, Wang F, Xiao Y, Zhang N . Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat Cell Biol. 2021; 23(1):87-98. DOI: 10.1038/s41556-020-00613-6. View

10.

Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford A . TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest. 2007; 117(12):3833-45. PMC: 2066188. DOI: 10.1172/JCI32567. View

11.

Choi S, Kim A, Nam J, Kim J, Kim J, Seo H . Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6 cancer cell and macrophage polarization. Nat Commun. 2018; 9(1):5108. PMC: 6269447. DOI: 10.1038/s41467-018-07470-w. View

12.

McAllister S, Gifford A, Greiner A, Kelleher S, Saelzler M, Ince T . Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell. 2008; 133(6):994-1005. PMC: 4121664. DOI: 10.1016/j.cell.2008.04.045. View

13.

Li M, Flavell R . TGF-beta: a master of all T cell trades. Cell. 2008; 134(3):392-404. PMC: 3677783. DOI: 10.1016/j.cell.2008.07.025. View

14.

Ai L, Xu A, Xu J . Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020; 1248:33-59. DOI: 10.1007/978-981-15-3266-5_3. View

15.

Welch-Reardon K, Wu N, Hughes C . A role for partial endothelial-mesenchymal transitions in angiogenesis?. Arterioscler Thromb Vasc Biol. 2014; 35(2):303-8. PMC: 4911209. DOI: 10.1161/ATVBAHA.114.303220. View

16.

Cremasco V, Astarita J, Grauel A, Keerthivasan S, MacIsaac K, Woodruff M . FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors. Cancer Immunol Res. 2018; 6(12):1472-1485. PMC: 6597261. DOI: 10.1158/2326-6066.CIR-18-0098. View

17.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

18.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

19.

Hong F, Meng Q, Zhang W, Zheng R, Li X, Cheng T . Single-Cell Analysis of the Pan-Cancer Immune Microenvironment and scTIME Portal. Cancer Immunol Res. 2021; 9(8):939-951. DOI: 10.1158/2326-6066.CIR-20-1026. View

20.

Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y . A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3):792-809.e23. DOI: 10.1016/j.cell.2021.01.010. View