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Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant

Heterogeneity of cancer-associated fibroblasts (CAFs) can result from activation of distinct signaling pathways. We show that in primary human dermal fibroblasts (HDFs), fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) signaling oppositely modulate multiple CAF effector genes....

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Autores principales: Bordignon, Pino, Bottoni, Giulia, Xu, Xiaoying, Popescu, Alma S., Truan, Zinnia, Guenova, Emmanuella, Kofler, Lukas, Jafari, Paris, Ostano, Paola, Röcken, Martin, Neel, Victor, Dotto, G. Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718812/
https://www.ncbi.nlm.nih.gov/pubmed/31461652
http://dx.doi.org/10.1016/j.celrep.2019.07.092
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author Bordignon, Pino
Bottoni, Giulia
Xu, Xiaoying
Popescu, Alma S.
Truan, Zinnia
Guenova, Emmanuella
Kofler, Lukas
Jafari, Paris
Ostano, Paola
Röcken, Martin
Neel, Victor
Dotto, G. Paolo
author_facet Bordignon, Pino
Bottoni, Giulia
Xu, Xiaoying
Popescu, Alma S.
Truan, Zinnia
Guenova, Emmanuella
Kofler, Lukas
Jafari, Paris
Ostano, Paola
Röcken, Martin
Neel, Victor
Dotto, G. Paolo
author_sort Bordignon, Pino
collection PubMed
description Heterogeneity of cancer-associated fibroblasts (CAFs) can result from activation of distinct signaling pathways. We show that in primary human dermal fibroblasts (HDFs), fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) signaling oppositely modulate multiple CAF effector genes. Genetic abrogation or pharmacological inhibition of either pathway results in induction of genes responsive to the other, with the ETV1 transcription factor mediating the FGF effects. Duality of FGF/TGF-β signaling and differential ETV1 expression occur in multiple CAF strains and fibroblasts of desmoplastic versus non-desmoplastic skin squamous cell carcinomas (SCCs). Functionally, HDFs with opposite TGF-β versus FGF modulation converge on promoting cancer cell proliferation. However, HDFs with increased TGF-β signaling enhance invasive properties and epithelial-mesenchymal transition (EMT) of SCC cells, whereas HDFs with increased FGF signaling promote macrophage infiltration. The findings point to a duality of FGF versus TGF-β signaling in distinct CAF populations that promote cancer development through modulation of different processes.
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spelling pubmed-67188122019-09-06 Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant Bordignon, Pino Bottoni, Giulia Xu, Xiaoying Popescu, Alma S. Truan, Zinnia Guenova, Emmanuella Kofler, Lukas Jafari, Paris Ostano, Paola Röcken, Martin Neel, Victor Dotto, G. Paolo Cell Rep Article Heterogeneity of cancer-associated fibroblasts (CAFs) can result from activation of distinct signaling pathways. We show that in primary human dermal fibroblasts (HDFs), fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) signaling oppositely modulate multiple CAF effector genes. Genetic abrogation or pharmacological inhibition of either pathway results in induction of genes responsive to the other, with the ETV1 transcription factor mediating the FGF effects. Duality of FGF/TGF-β signaling and differential ETV1 expression occur in multiple CAF strains and fibroblasts of desmoplastic versus non-desmoplastic skin squamous cell carcinomas (SCCs). Functionally, HDFs with opposite TGF-β versus FGF modulation converge on promoting cancer cell proliferation. However, HDFs with increased TGF-β signaling enhance invasive properties and epithelial-mesenchymal transition (EMT) of SCC cells, whereas HDFs with increased FGF signaling promote macrophage infiltration. The findings point to a duality of FGF versus TGF-β signaling in distinct CAF populations that promote cancer development through modulation of different processes. Cell Press 2019-08-27 /pmc/articles/PMC6718812/ /pubmed/31461652 http://dx.doi.org/10.1016/j.celrep.2019.07.092 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bordignon, Pino
Bottoni, Giulia
Xu, Xiaoying
Popescu, Alma S.
Truan, Zinnia
Guenova, Emmanuella
Kofler, Lukas
Jafari, Paris
Ostano, Paola
Röcken, Martin
Neel, Victor
Dotto, G. Paolo
Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title_full Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title_fullStr Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title_full_unstemmed Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title_short Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
title_sort dualism of fgf and tgf-β signaling in heterogeneous cancer-associated fibroblast activation with etv1 as a critical determinant
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718812/
https://www.ncbi.nlm.nih.gov/pubmed/31461652
http://dx.doi.org/10.1016/j.celrep.2019.07.092
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