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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122372 | GEO | 2019/07/31

REPOSITORIES: GEO

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Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (DNFGFR1_affy)

Project description: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.

2019-07-31 | GSE122371 | GEO

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

2019-07-31 | GSE122370 | GEO

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_65_HDF)

2019-07-31 | GSE122369 | GEO

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_FGF2)

2019-07-31 | GSE122368 | GEO

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

Project description:Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development

| PRJNA504805 | ENA

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (DNFGFR1_affy)

Project description:Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (DNFGFR1_affy)

| PRJNA504813 | ENA

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

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

| PRJNA504812 | ENA

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_65_HDF)

Project description:Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_65_HDF)

| PRJNA504811 | ENA

Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_FGF2)

Project description:Dualism of FGF and TGFb signaling in activation of heterogeneous cancer-associated fibroblast populations converging on cancer development (RNA-Seq_FGF2)

| PRJNA504810 | ENA

Human FGF-21 Is a Substrate of Fibroblast Activation Protein.

Project description:FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half-life of active, circulating, human FGF-21 has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-specific inhibitor, ARI-3099, blocks the activity in mouse, monkey and human plasma and prolongs the half-life of circulating human FGF-21 in mice. Mouse FGF-21, however, lacks the FAP cleavage site and is not cleaved by FAP. These findings indicate FAP may function in the regulation of metabolism and that FAP inhibitors may prove useful in the treatment of diabetes and metabolic disorders in humans, but pre-clinical proof of concept studies in rodents will be problematic.

| S-EPMC4786124 | biostudies-literature

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