Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment

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

doi:10.1038/s41598-023-28480-9

Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment

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

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28 Scopus citations

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.

Original language	English
Article number	3051
Journal	Scientific Reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-28480-9
State	Published - Dec 2023
Externally published	Yes

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Szabo, P. M., Vajdi, A., Kumar, N., Tolstorukov, M. Y., Chen, B. J., Edwards, R., Ligon, K. L., Chasalow, S. D., Chow, K. H., Shetty, A., Bolisetty, M., Holloway, J. L., Golhar, R., Kidd, B. A., Hull, P. A., Houser, J., Vlach, L., Siemers, N. O., & Saha, S. (2023). Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment. Scientific Reports, 13(1), Article 3051. https://doi.org/10.1038/s41598-023-28480-9

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title = "Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment",

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.",

author = "Szabo, {Peter M.} and Amir Vajdi and Namit Kumar and Tolstorukov, {Michael Y.} and Chen, {Benjamin J.} and Robin Edwards and Ligon, {Keith L.} and Chasalow, {Scott D.} and Chow, {Kin Hoe} and Aniket Shetty and Mohan Bolisetty and Holloway, {James L.} and Ryan Golhar and Kidd, {Brian A.} and Hull, {Philip Ansumana} and Jeff Houser and Logan Vlach and Siemers, {Nathan O.} and Saurabh Saha",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41598-023-28480-9",

language = "English",

volume = "13",

journal = "Scientific Reports",

issn = "2045-2322",

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Szabo, PM, Vajdi, A, Kumar, N, Tolstorukov, MY, Chen, BJ, Edwards, R, Ligon, KL, Chasalow, SD, Chow, KH, Shetty, A, Bolisetty, M, Holloway, JL, Golhar, R, Kidd, BA, Hull, PA, Houser, J, Vlach, L, Siemers, NO & Saha, S 2023, 'Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment', Scientific Reports, vol. 13, no. 1, 3051. https://doi.org/10.1038/s41598-023-28480-9

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AU - Szabo, Peter M.

AU - Vajdi, Amir

AU - Kumar, Namit

AU - Tolstorukov, Michael Y.

AU - Chen, Benjamin J.

AU - Edwards, Robin

AU - Ligon, Keith L.

AU - Chasalow, Scott D.

AU - Chow, Kin Hoe

AU - Shetty, Aniket

AU - Bolisetty, Mohan

AU - Holloway, James L.

AU - Golhar, Ryan

AU - Kidd, Brian A.

AU - Hull, Philip Ansumana

AU - Houser, Jeff

AU - Vlach, Logan

AU - Siemers, Nathan O.

AU - Saha, Saurabh

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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JO - Scientific Reports

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Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment

Abstract

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