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

Abstract

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