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Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant.
Cell Reports ( IF 7.5 ) Pub Date : 2019-08-27 , DOI: 10.1016/j.celrep.2019.07.092 Pino Bordignon 1 , Giulia Bottoni 2 , Xiaoying Xu 1 , Alma S Popescu 1 , Zinnia Truan 3 , Emmanuella Guenova 4 , Lukas Kofler 5 , Paris Jafari 6 , Paola Ostano 7 , Martin Röcken 5 , Victor Neel 8 , G Paolo Dotto 6
Cell Reports ( IF 7.5 ) Pub Date : 2019-08-27 , DOI: 10.1016/j.celrep.2019.07.092 Pino Bordignon 1 , Giulia Bottoni 2 , Xiaoying Xu 1 , Alma S Popescu 1 , Zinnia Truan 3 , Emmanuella Guenova 4 , Lukas Kofler 5 , Paris Jafari 6 , Paola Ostano 7 , Martin Röcken 5 , Victor Neel 8 , G Paolo Dotto 6
Affiliation
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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.
中文翻译：
FGF和TGF-β信号转导的二元性在以ETV1为关键决定因素的异种癌相关的成纤维细胞激活中。
癌症相关成纤维细胞（CAF）的异质性可能是由于不同信号通路的激活所致。我们显示在原代人皮肤成纤维细胞（HDFs）中，成纤维细胞生长因子（FGF）和转化生长因子β（TGF-β）信号相反地调节多个CAF效应子基因。对任一途径的遗传废除或药理学抑制作用导致诱导对另一种途径有响应的基因，而ETV1转录因子介导FGF效应。FGF /TGF-β信号转导和ETV1差异表达的双重性发生在成年性和非成年性皮肤鳞状细胞癌（SCC）的多个CAF菌株和成纤维细胞中。在功能上，具有相反的TGF-β和FGF调节作用的HDF集中在促进癌细胞增殖上。然而，TGF-β信号增强的HDF增强SCC细胞的侵袭性和上皮-间质转化（EMT），而FGF信号增强的HDF促进巨噬细胞浸润。这些发现指出，在不同的CAF人群中FGF与TGF-β信号的双重性通过调节不同的过程促进了癌症的发展。
更新日期：2019-08-27
中文翻译：
FGF和TGF-β信号转导的二元性在以ETV1为关键决定因素的异种癌相关的成纤维细胞激活中。
癌症相关成纤维细胞（CAF）的异质性可能是由于不同信号通路的激活所致。我们显示在原代人皮肤成纤维细胞（HDFs）中，成纤维细胞生长因子（FGF）和转化生长因子β（TGF-β）信号相反地调节多个CAF效应子基因。对任一途径的遗传废除或药理学抑制作用导致诱导对另一种途径有响应的基因，而ETV1转录因子介导FGF效应。FGF /TGF-β信号转导和ETV1差异表达的双重性发生在成年性和非成年性皮肤鳞状细胞癌（SCC）的多个CAF菌株和成纤维细胞中。在功能上，具有相反的TGF-β和FGF调节作用的HDF集中在促进癌细胞增殖上。然而，TGF-β信号增强的HDF增强SCC细胞的侵袭性和上皮-间质转化（EMT），而FGF信号增强的HDF促进巨噬细胞浸润。这些发现指出，在不同的CAF人群中FGF与TGF-β信号的双重性通过调节不同的过程促进了癌症的发展。
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