Epithelial-mesenchymal interactions play an important function in control of skin homeostasis. The increase of cancer risk associated with aging has been connected with the induction of many growth factors, pro- inflammatory cytokines and extracellular matrix proteins synthesized during senescence that are also produced by Cancer Associated Fibroblasts (CAFs). Reduced testosterone levels and AR signaling have been connected with the aging process at multiple levels but little is known on the role of androgen receptor (AR) signaling in conversion of stromal fibroblasts into CAFs. We have recently shown that compromised Notch/CSL signaling in dermal fibroblasts leads to CAF conversion with ensuing chronic inflammation and premalignant and malignant keratinocyte lesions. Our overall working hypothesis is that AR signaling plays an important negative role in dermal fibroblast to CAF conversion, as part of a cross-talk with Notch/CSL signaling that is of translational significance. The following specific aims will be pursued: We will test the hypothesis that dermal AR signaling suppresses conversion of normal dermal fibroblasts into CAFs. We have found that AR expression is significantly down-modulated in stromal fibroblasts underlying premalignant (Actinic Keratosis, AK) and malignant (SCC) skin lesions. Functionally, AR gene silencing in human dermal fibroblasts (HDFs) causes up-regulation of key CAF-effector genes and induces cancer- promoting properties We will test the hypothesis that AR and CSL signaling converge in negative control of CAF activation. By RNA- seq analysis, we have found a significant overlap of deregulated genes of functional significance in HDFs with AR versus CSL gene silencing. We have further observed that silencing of either the CSL or AR gene leads to decreased expression of the other. We will test the hypothesis that up-regulation of AR expression and/or activity can revert CAF activation and suppress skin tumor development and/or expansion. Our preliminary findings indicate that AR expression in HDFs plus/minus CSL silencing and in clinically-derived CAFs is down-modulated at the transcriptional level. We have further found that inhibitors of BET proteins ? which link the basal apparatus to acetylated histones and other regulators of transcription - induce AR gene transcription at the same time that they suppress a large spectrum of CAF effector genes and that AR agonists exert similar inhibitory effects on CAF genes.
Interactions between cells of the dermal and epidermal compartment play an important role in control of skin homeostasis, with dermal changes having a determining function in various pathologies including pre-malignant and malignant cancer development. Reduced testosterone levels and androgen receptor (AR) signaling have been connected with the aging process, which is linked to an exponential increase in cancer risk. Our main working hypothesis is that AR signaling plays an essential role in the mesenchymal compartment of the skin, controlling acquisition by normal dermal fibroblasts of cancer enhancing properties on overlying keratinocytes.
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