Molecular aging in sun-damaged skin

• Applicant: Dr. Yannick Foerster
• Subject Area: Dermatology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577276302

Overview: Each year, 85,000 people are diagnosed with non-melanoma skin cancer (NMSC), including cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), in Germany. The incidence is likely to increase over the next years due to demographic changes. Over 80% of patients with a BCC or cSCC will develop new skin cancers on the same body site of sun damage within 5 years of their first cancer. This ongoing development of skin cancers in the same site is related to field cancerization. While most current surgical interventions result in complete remission of individual lesions, they do not prevent the onset of new lesions and therefore the need for further surveillance and surgery remains. We urgently need to reduce the onset of new cancers from sun-damaged skin to durably reduce the burden of disease. Current knowledge gap: The vast majority of NMSCs occur after the age of 60. This has been attributed to cumulative sun damage and linked to accumulation of DNA mutations. However, at the biological level, the link between skin cancer and aging is not well understood. Researchers from the Frazer Institute have developed preliminary evidence that aging results in epigenetic changes that may favor carcinogenesis via an altered epidermal response to UV radiation, radically changing how we understand skin carcinogenesis. Hypothesis and Aims: In this application, we will establish for the first time a molecular link between epidermal aging and skin cancer development. The host lab has previously shown that keratinocyte aging is driven by Activator Protein 1 (AP-1)-linked chromatin opening, which results in the rewiring of developmental and differentiation genes. We hypothesize that this cell-intrinsic chromatin remodeling with age, possibly related to the age- altered systemic environment, allows excessive AP-1-driven proliferation, a classical hallmark of epidermal response to UV irradiation. We also hypothesize that inhibition of AP-1 binding in this context can restore normal epidermal proliferation and differentiation and hence reduce UV induced skin carcinogenesis. Our specific aims are: Aim 1: To dissect the aged host environment’s role on clonal dynamics of epidermis in response to UV radiation. Aim 2: To interrogate AP-1 driven chromatin opening via single cell multiome profiling in aged versus young epidermis, exposed or not to chronic UVB irradiation. Aim 3: To examine the impact of genetic or pharmacological AP-1 inhibition on epidermal proliferation and carcinogenesis. Significance: Researchers from the Frazer Institute have identified an age-driven mechanism - AP-1-mediated chromatin opening in epidermal cells - that may accelerate epidermal clonal expansion similarly to chronic UV exposure. This project will define how aging and UV jointly contribute to skin carcinogenesis and will explore genetic and pharmacological AP-1 inhibition for urgently needed novel chemo-preventive approaches.

• DFG Programme: WBP Fellowship
• International Connection: Australia
• Host: Professor Dr. Kiarash Khosrotehrani