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

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

PROVIDER: PRJNA504805 | ENA |

REPOSITORIES: ENA

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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_FGF2)

2019-07-31 | GSE122368 | 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 (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 (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 (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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-07-31 | GSE122372 | GEO

Profiling of Y1 cells treated with FGF-2 reveals parallels with oncogene-induced senescence

Project description:Paradoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Along these lines, Y1 cells, which carry an amplification of Ras, become senescent after treatment with the mitogen FGF-2. To understand how FGF-2 promotes senescence, we profiled the epigenome, transcriptome, proteome, and phospho-proteome of Y1 cells stimulated with FGF-2. FGF-2 caused delayed acetylation of histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. In contrast, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. Altogether, the response of Y1 cells to FGF-2 is consistent with oncogene-induced senescence. We propose that Y1 cells enter senescence due to deficient cyclin expression and high levels of p21, which may stem from DNA damage or TGFb signaling.

2021-06-16 | PXD020688 | Pride

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