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

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

Summary: 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 effect...

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Main Authors: Pino Bordignon, Giulia Bottoni, Xiaoying Xu, Alma S. Popescu, Zinnia Truan, Emmanuella Guenova, Lukas Kofler, Paris Jafari, Paola Ostano, Martin Röcken, Victor Neel, G. Paolo Dotto
Format: Article
Language:English
Published: Elsevier 2019-08-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124719310083
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spelling doaj-16e7573a3e1445219de1a405631deb3f2020-11-25T01:58:48ZengElsevierCell Reports2211-12472019-08-0128923582372.e6Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical DeterminantPino Bordignon0Giulia Bottoni1Xiaoying Xu2Alma S. Popescu3Zinnia Truan4Emmanuella Guenova5Lukas Kofler6Paris Jafari7Paola Ostano8Martin Röcken9Victor Neel10G. Paolo Dotto11Department of Biochemistry, University of Lausanne, Epalinges 1066, SwitzerlandDepartment of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USADepartment of Biochemistry, University of Lausanne, Epalinges 1066, SwitzerlandDepartment of Biochemistry, University of Lausanne, Epalinges 1066, SwitzerlandDepartment of Otolaryngology-Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne 1011, SwitzerlandDepartment of Dermatology, University Hospital Zurich, University of Zurich, Zurich 8091, SwitzerlandDepartment of Dermatology, Eberhard Karls University, Tübingen 72076, GermanyDepartment of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA; International Cancer Prevention Institute, Epalinges 1066, SwitzerlandCancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella 13900, ItalyDepartment of Dermatology, Eberhard Karls University, Tübingen 72076, GermanyDepartment of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA; International Cancer Prevention Institute, Epalinges 1066, Switzerland; Corresponding authorSummary: 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. : Bordignon et al. show that activation of FGF and TGF-β control opposite key CAF effectors. Suppression of one pathway leads to activation of the other and results in tumor-promoting CAF populations that elicit EMT versus inflammation. FGF/TGF-β dualism applies to distinct CAF subsets in invading desmoplastic versus non-desmoplastic skin SCCs. Keywords: cancer-associated fibroblasts, CAF, FGF, TGF-β, ETV1, skin cancer, SCC, EMT, inflammation, macrophageshttp://www.sciencedirect.com/science/article/pii/S2211124719310083
collection DOAJ
language English
format Article
sources DOAJ
author Pino Bordignon
Giulia Bottoni
Xiaoying Xu
Alma S. Popescu
Zinnia Truan
Emmanuella Guenova
Lukas Kofler
Paris Jafari
Paola Ostano
Martin Röcken
Victor Neel
G. Paolo Dotto
spellingShingle Pino Bordignon
Giulia Bottoni
Xiaoying Xu
Alma S. Popescu
Zinnia Truan
Emmanuella Guenova
Lukas Kofler
Paris Jafari
Paola Ostano
Martin Röcken
Victor Neel
G. Paolo Dotto
Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant
Cell Reports
author_facet Pino Bordignon
Giulia Bottoni
Xiaoying Xu
Alma S. Popescu
Zinnia Truan
Emmanuella Guenova
Lukas Kofler
Paris Jafari
Paola Ostano
Martin Röcken
Victor Neel
G. Paolo Dotto
author_sort Pino Bordignon
title 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_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_sort dualism of fgf and tgf-β signaling in heterogeneous cancer-associated fibroblast activation with etv1 as a critical determinant
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2019-08-01
description Summary: 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. : Bordignon et al. show that activation of FGF and TGF-β control opposite key CAF effectors. Suppression of one pathway leads to activation of the other and results in tumor-promoting CAF populations that elicit EMT versus inflammation. FGF/TGF-β dualism applies to distinct CAF subsets in invading desmoplastic versus non-desmoplastic skin SCCs. Keywords: cancer-associated fibroblasts, CAF, FGF, TGF-β, ETV1, skin cancer, SCC, EMT, inflammation, macrophages
url http://www.sciencedirect.com/science/article/pii/S2211124719310083
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