Cancer-associated Fibroblasts Are the Main Contributors to Epithelial-to-mesenchymal Signatures in the Tumor Microenvironment

Overview

Journal Sci Rep

Specialty Science

Date 2023 Feb 22

PMID 36810872

Authors

Peter M Szabo

Amir Vajdi

Namit Kumar

Michael Y Tolstorukov

Benjamin J Chen

Robin Edwards

Keith L Ligon

Scott D Chasalow

Kin-Hoe Chow

Aniket Shetty

Mohan Bolisetty

James L Holloway

Ryan Golhar

Brian A Kidd

Philip Ansumana Hull

Jeff Houser

Logan Vlach

Nathan O Siemers

Saurabh Saha

Affiliations

Soon will be listed here.

Abstract

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature (COL1A1, COL1A2, COL3A1) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies.

Citing Articles

Hidradenitis Suppurativa Tunnels: Unveiling a Unique Disease Entity.

Vecin N, Balukoff N, Yaghi M, Gonzalez T, Sawaya A, Strbo N JID Innov. 2025; 5(3):100350.

PMID: 40034103 PMC: 11872476. DOI: 10.1016/j.xjidi.2025.100350.

A Simple Framework for Agent-Based Modeling with Extracellular Matrix.

Metzcar J, Duggan B, Fischer B, Murphy M, Heiland R, Macklin P Bull Math Biol. 2025; 87(3):43.

PMID: 39937344 PMC: 11821717. DOI: 10.1007/s11538-024-01408-8.

Studying breast cancer lung metastasis using a multi-compartment microfluidic device with a mimetic tumor-stroma interaction model.

Zarin B, Rafiee L, Abdollahi S, Vatani M, Hassani M, Sanati-Nezhad A Transl Oncol. 2025; 53:102303.

PMID: 39904278 PMC: 11847141. DOI: 10.1016/j.tranon.2025.102303.

Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.

Glaviano A, Lau H, Carter L, Lee E, Lam H, Okina E J Hematol Oncol. 2025; 18(1):6.

PMID: 39806516 PMC: 11733683. DOI: 10.1186/s13045-024-01634-6.

The Complexity and Significance of Fibroblast Growth Factor (FGF) Signaling for FGF-Targeted Cancer Therapies.

Nguyen A, Facey C, Boman B Cancers (Basel). 2025; 17(1.

PMID: 39796710 PMC: 11720651. DOI: 10.3390/cancers17010082.

References

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian Z, Du J . Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487(7408):500-4. PMC: 3711467. DOI: 10.1038/nature11183. View

Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W . FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. Cancer Res. 2016; 76(14):4124-35. DOI: 10.1158/0008-5472.CAN-15-2973. View

Gao H, Korn J, Ferretti S, Monahan J, Wang Y, Singh M . High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med. 2015; 21(11):1318-25. DOI: 10.1038/nm.3954. View

Ruhland M, Loza A, Capietto A, Luo X, Knolhoff B, Flanagan K . Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016; 7:11762. PMC: 4899869. DOI: 10.1038/ncomms11762. View

Ahmadzadeh M, Rosenberg S . TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol. 2005; 174(9):5215-23. PMC: 2562293. DOI: 10.4049/jimmunol.174.9.5215. View

Yu M, Bardia A, Wittner B, Stott S, Smas M, Ting D . Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013; 339(6119):580-4. PMC: 3760262. DOI: 10.1126/science.1228522. View

Desbois M, Udyavar A, Ryner L, Kozlowski C, Guan Y, Durrbaum M . Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat Commun. 2020; 11(1):5583. PMC: 7642433. DOI: 10.1038/s41467-020-19408-2. 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

Derose Y, Wang G, Lin Y, Bernard P, Buys S, Ebbert M . Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011; 17(11):1514-20. PMC: 3553601. DOI: 10.1038/nm.2454. View

10.

Hanley C, Noble F, Ward M, Bullock M, Drifka C, Mellone M . A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers. Oncotarget. 2015; 7(5):6159-74. PMC: 4868747. DOI: 10.18632/oncotarget.6740. View

11.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

12.

Keysar S, Astling D, Anderson R, Vogler B, Bowles D, Morton J . A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol. 2013; 7(4):776-90. PMC: 3760013. DOI: 10.1016/j.molonc.2013.03.004. View

13.

Zhang X, Claerhout S, Prat A, Dobrolecki L, Petrovic I, Lai Q . A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res. 2013; 73(15):4885-97. PMC: 3732575. DOI: 10.1158/0008-5472.CAN-12-4081. View

14.

Ribatti D, Tamma R, Annese T . Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol. 2020; 13(6):100773. PMC: 7182759. DOI: 10.1016/j.tranon.2020.100773. View

15.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

16.

Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C . A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2012; 1(6):508-23. DOI: 10.1158/2159-8290.CD-11-0109. View

17.

Jena B, Das C, Banerjee I, Das S, Bharadwaj D, Majumder R . Paracrine TGF-β1 from breast cancer contributes to chemoresistance in cancer associated fibroblasts via upregulation of the p44/42 MAPK signaling pathway. Biochem Pharmacol. 2021; 186:114474. DOI: 10.1016/j.bcp.2021.114474. View

18.

Verrecchia F, Chu M, Mauviel A . Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001; 276(20):17058-62. DOI: 10.1074/jbc.M100754200. View

19.

Sivanand S, Pena-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A . A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med. 2012; 4(137):137ra75. PMC: 3570965. DOI: 10.1126/scitranslmed.3003643. View

20.

Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D . Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013; 110(50):20212-7. PMC: 3864274. DOI: 10.1073/pnas.1320318110. View