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Pten loss induces autocrine FGF signaling to promote skin tumorigenesis.

ABSTRACT: 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.

SUBMITTER: Hertzler-Schaefer K

PROVIDER: S-EPMC4080841 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Pten loss induces autocrine FGF signaling to promote skin tumorigenesis.

Hertzler-Schaefer Kristina K Mathew Grinu G Somani Ally-Khan AK Tholpady Sunil S Kadakia Madhavi P MP Chen Yiping Y Spandau Dan F DF Zhang Xin X

Cell reports 20140227 5

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 cause ...[more]

PMID: 24582960

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Project description:Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a direct antagonist of phosphatidylinositol 3 kinase. Pten is a well recognized tumor suppressor and is one of the most commonly mutated genes in human malignancies. More recent studies of development and stem cell behavior have shown that PTEN regulates the growth and differentiation of progenitor cells. Significantly, PTEN is found in osteoprogenitor cells that give rise to bone-forming osteoblasts; however, the role of PTEN in bone development is incompletely understood. To define how PTEN functions in osteoprogenitors during bone development, we conditionally deleted Pten in mice using the cre-deleter strain Dermo1cre, which targets undifferentiated mesenchyme destined to form bone. Deletion of Pten in osteoprogenitor cells led to increased numbers of osteoblasts and expanded bone matrix. Significantly, osteoblast development and synthesis of osteoid in the nascent bone collar was uncoupled from the usual tight linkage to chondrocyte differentiation in the epiphyseal growth plate. The expansion of osteoblasts and osteoprogenitors was found to be due to augmented FGF signaling as evidenced by (1) increased expression of FGF18, a potent osteoblast mitogen, and (2) decreased expression of SPRY2, a repressor of FGF signaling. The differentiation of osteoblasts was autonomous from the growth plate chondrocytes and was correlated with an increase in the protein levels of GLI2, a transcription factor that is a major mediator of hedgehog signaling. We provide evidence that increased GLI2 activity is also a consequence of increased FGF signaling through downstream events requiring mitogen-activated protein kinases. To test whether FGF signaling is required for the effects of Pten deletion, we deleted one allele of fibroblast growth factor receptor 2 (FGFR2). Significantly, deletion of FGFR2 caused a partial rescue of the Pten-null phenotype. This study identifies activated FGF signaling as the major mediator of Pten deletion in osteoprogenitors.

Dataset Information

Pten loss induces autocrine FGF signaling to promote skin tumorigenesis.

Publications

Pten loss induces autocrine FGF signaling to promote skin tumorigenesis.

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