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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122369 | 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 (RNA-Seq_FGF2)

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.

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