Exogenous insults, like UV exposure, lead to skin changes associated with aging and increased cancer risk. We recently showed that compromised Notch/CSL signaling, in dermal fibroblasts can lead to cutaneous field cancerization, an important clinical condition, consisting of multifocal premalignant keratinocyte lesions (like actinic keratosis, AK) preceded by more widespread changes in surrounding epithelial and stromal tissues. In preliminary studies we have found that, in stroma of AK lesions in which matrix remodeling and pro-inflammatory genes are up-regulated, expression of ATF3 is decreased. ATF3 is a key stress response transcription factor with a tumor promoting function in keratinocytes. Our working hypothesis is that ATF3 plays an opposite function in dermal cells, maintaining normal skin homeostasis and suppressing keratinocyte tumor progression. 1) We will test the hypothesis that dermal fibroblast expression of ATF3 plays a suppressive function against keratinocyte tumor development. In our preliminary work we have found that mice with ubiquitous ATF3 gene deletion have increased susceptibility to dysplastic/malignant skin tumor formation and that ATF3 -/- dermal fibroblasts enhance tumorigenic behavior of weakly transformed keratinocytes. We will extend the findings by analysis of mice with dermal fibroblast- specific deletion of the ATF3 gene and extend the results to human cells, utilizing a novel in vivo imaging assay for tumor expansion that we have developed. 2) We will test the hypothesis that ATF3 is involved in control of dermal fibroblast senescence and CAF activation in antagonism with compromised Notch/CSL signaling. Stromal cells senescence results in production of diffusible factors inducing paracrine tumor growth stimulation. We have found that, in dermal fibroblasts, many senescence and CAF (S-CAF) genes are up-regulated by ATF3 silencing, while increased ATF3 suppresses their expression. We will assess whether ATF3 controls expression of these genes by direct binding in parallel with Notch/CSL and/or functioning in concert with other transcription repressing mechanisms. 3) We will test the hypothesis that methods involving up-regulation of ATF3 expression and/or function can be used for suppression of dermal fibroblast senescence and/or CAF activation. Efficacy of compounds identified by in vitro assays will be validated in vivo, in animal models and by use of human cell imaging assays.
ATF3 is a key stress response transcription factor with highly cell type-dependent biological functions. Our main working hypothesis is that this transcription factor plays an essential role in the mesenchymal compartment of the skin, with an impact on dermal fibroblast senescence and dermal aging-associated changes, as well as on paracrine control of keratinocyte proliferation and tumor development.
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