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Abstract

Non-melanoma skin cancer (NMSC) is the most common malignancy in the fair-skinned population and represents a tremendous limitation in the quality of life, especially for organ transplant recipients and in patients suffering from Epidermodysplasia verruciformis. Epidemiological studies support a role of human papillomavirus (HPV) in the development of NMSC. In the study presented here, the African multimammate mouse Mastomys coucha, which is naturally infected with the host-species specific Mastomys natalensis papillomavirus (MnPV), is used as a preclinical model system. It is already known that MnPV, together with UV light, is involved in the formation of NMSC in Mastomys through a "hit- and-run" mechanism. However, until now it was unknown which processes in the cell underlie this effect. In the work presented here, new insights into the interplay between MnPV and the target cell were uncovered. Thus, for the first time, spatial proteomes of different NMSC subtypes were analyzed in the context of tumor heterogeneity. Here, large differences in protein expression patterns between subtypes emerged. This provides novel and profound insights into the inter-/ and intra-tumor heterogeneity of NMSCs. Moreover, based on in vitro proteomic studies, the influence of MnPV oncoproteins on signal transduction pathways of diverse cellular processes could be demonstrated. Interactome studies revealed several host cellular interactors of the MnPV oncoproteins E6 and E7. Previously known binding partners (Maml1 of MnPVE6) were confirmed but also new interaction partners such as Smad2/3 (MnPVE6) and PtpN14 (MnPVE7) were described for the first time. Using a top-down approach, an effect of MnPV on the HIPPO pathway was observed in MnPV-infected cell systems. In another in vitro system, this effect could be attributed to the oncoprotein E7, which has a reducing effect on the expression level of PtpN14, a phosphatase belonging to the HIPPO pathway. The main effectors of this signaling pathway Yap/Taz, were increasingly translocated to the nucleus in MnPVE7- and MnPVE6E7-expressing cells due to reduced PtpN14 expression. This effect was demonstrated for the first time for a cutaneous PV type in this work. In summary, this work reveals new insights into the interaction between MnPV and the host cell. These aspects of cutaneous PV infection represent interesting new starting points for further investigation of the genesis of NMSCs.