Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (CAF_vs_Norm_affy)

The molecular basis for heterogeneity of cancer-associated fibroblast (CAF) populations remains to be established. We report that fibroblast growth factor (FGF) and transforming growth factor-beta (TGFB) signaling are strong opposite modulators of key CAF effector genes. While FGF activation in normal human dermal fibroblasts (HDFs) induces a number of mitogenic growth factors and metalloproteases, it suppresses expression of pro-fibrotic and cancer-associated extracellular matrix proteins, with TGFB exerting reverse effects. Genetic abrogation or pharmacological inhibition of either pathway results in induction of CAF effector genes responsive to the other, with the ETV1 transcription factor mediating FGF effects and suppressing those of TGFB. This duality of FGF- and TGFB- signaling is reflected in the distinct gene expression profiles of HDFs derived from a large cohort of individuals, multiple Squamous Cell Carcinoma (SCC)-derived CAF strains and stromal fibroblasts underlying premalignant (Actinic Keratoses) and desmoplastic versus non-desmoplastic skin SCC lesions. Functionally, an altered balance between FGF or TGFB signaling, by genetic suppression of either, is sufficient to confer upon HDFs growth enhancing properties on neighboring SCC cells, in vitro and in vivo, in an orthotopic skin cancer model. Thus, activation of heterogeneous CAF populations by deregulation of distinct signaling pathways converges on cancer development with implications of translational significance. Gene expression profiling of 8 skin cancer-associated fibroblast (CAF) strains and normal fibroblasts from matched donors.

肿瘤相关成纤维细胞（cancer-associated fibroblast, CAF）群体异质性的分子基础仍有待阐明。本研究报道，成纤维细胞生长因子（fibroblast growth factor, FGF）与转化生长因子-β（transforming growth factor-beta, TGFB）信号通路是关键CAF效应基因的强效反向调控因子。在正常人皮肤成纤维细胞（normal human dermal fibroblasts, HDFs）中，FGF激活可诱导多种促有丝分裂生长因子及金属蛋白酶，同时抑制促纤维化与肿瘤相关细胞外基质蛋白的表达；而TGFB则发挥完全相反的调控作用。敲除任一通路或对其进行药物抑制，均可诱导受另一通路调控的CAF效应基因表达，其中ETV1转录因子介导FGF的调控效应并抑制TGFB的作用。FGF与TGFB信号通路的这种双向调控特性，在大队列个体来源的HDFs、多种鳞状细胞癌（squamous cell carcinoma, SCC）来源的CAF菌株，以及癌前病变（光化性角化病，Actinic Keratoses）、促纤维化型与非促纤维化型皮肤鳞状细胞癌病灶旁基质成纤维细胞的差异化基因表达谱中均有体现。功能实验表明，通过遗传抑制任一通路以改变FGF与TGFB信号的平衡，即可在体外实验及原位皮肤癌模型的体内实验中，赋予HDFs促进邻近SCC细胞增殖的能力。综上，通过失调不同信号通路而激活的异质性CAF群体，最终均会促进肿瘤发生，这一发现具有重要的转化研究价值。本数据集包含8株皮肤肿瘤相关成纤维细胞（CAF）菌株及匹配供体来源的正常成纤维细胞的基因表达谱数据。