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Abstract

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte cancer with a rapidly increasing incidence and one of the most common cancer types in the fair-skinned population. Chronic exposure to ultraviolet radiation (UVR) is its main risk factor and can lead to the development of a premalignant skin lesion, actinic keratosis (AK), which might further progress into cSCC. In addition, invasive cSCC can also develop from the in situ carcinoma Bowen’s disease (BD). During this progression, resident dermal fibroblasts are transformed into cancer-associated fibroblasts (CAFs) that are known to promote tumorigenesis. However, a detailed characterization of cSCC-related CAFs with respect to their fibroblast subpopulation-specific origin, heterogeneity, and tumor-promoting functions was still missing. Therefore, in this thesis, more than 115,000 single-cell transcriptomes from healthy human skin, BD and cSCC samples were analyzed. The results revealed two main CAF subpopulations with distinct functions and origins. Inflammatory CAFs (iCAFs) seemed to develop mainly from pro-inflammatory fibroblasts and presented immunoregulatory functions, including cellular interactions with immune cells in the tumor microenvironment (TME). On the other hand, myofibroblastic CAFs (myCAFs) were observed to originate mainly from healthy mesenchymal fibroblasts and were involved in extracellular matrix (ECM) remodeling processes. Furthermore, multiplexed RNA fluorescence in situ hybridization (FISH) assays not only confirmed both CAF subpopulations in human BD and cSCC, but also provided valuable information about the time window of CAF activation, as no CAFs could be observed in AK tissue sections. Interestingly, these findings could not be transferred to basal cell carcinoma (BCC), the second major keratinocyte cancer. Taken together, this thesis provides novel insights into CAF development, stratification, and functions during cSCC initiation and progression.