Pten Loss Induces Autocrine FGF Signaling to Promote Skin Tumorigenesis

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une activation autocrine de la signalisation FGF favorise le développement d'une tumeur cutanée associée à la perte du gène suppresseur de tumeurs PTEN

Résumé en anglais

Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 causes skin papillomas, whereas Pten deletion-induced skin tumors are inhibited by epidermal deletion of Fgfr2. Collectively, our data identify autocrine activation of FGF signaling as an essential mechanism in promoting Pten-deficient skin tumors.

"Pten deletion induces Fgf10 expression in skin epidermis
"Fgf10 is regulated at the translational level by mTORC1"Overexpression of Fgf10 reproduces skin papillomas
"PTEN deficiency in human cutaneous SCC correlates with higher FGF10 levels

Nonmelanoma skin cancer is the most prevalent cancer in the world. Zhang and colleagues now show that loss of Pten expression in keratinocytes leads to an mTORC1-dependent translational overexpression of Fgf10, which is sufficient to induce skin papillomas. Consistent with these results, skin tumorigenesis can be blocked by genetic ablation of either mTOR or FGF signaling. These data highlight the potential of FGF signaling components as therapeutic targets in PI3K-dependent skin cancer.