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

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

doi:10.1016/j.celrep.2019.07.092

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

Cell Rep. 2019 Aug 27;28(9):2358-2372.e6. doi: 10.1016/j.celrep.2019.07.092.

Authors

Affiliations

¹ Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland.
² Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
³ Department of Otolaryngology-Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne 1011, Switzerland.
⁴ Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland.
⁵ Department of Dermatology, Eberhard Karls University, Tübingen 72076, Germany.
⁶ Department 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.
⁷ Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella 13900, Italy.
⁸ Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Department 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. Electronic address: paolo.dotto@unil.ch.

Abstract

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.

Keywords: CAF; EMT; ETV1; FGF; SCC; TGF-β; cancer-associated fibroblasts; inflammation; macrophages; skin cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cancer-Associated Fibroblasts / metabolism*
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology
Cells, Cultured
Child, Preschool
DNA-Binding Proteins / metabolism*
Epithelial-Mesenchymal Transition
Female
Fibroblast Growth Factors / metabolism*
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Signal Transduction*
Skin Neoplasms / metabolism*
Skin Neoplasms / pathology
Transcription Factors / metabolism*
Transforming Growth Factor beta / metabolism*

Substances

DNA-Binding Proteins
ETV1 protein, human
Transcription Factors
Transforming Growth Factor beta
Fibroblast Growth Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding