Deciphering the Interplay of UV Radiation and Cutaneous Papillomavirus Infection in Non-Melanoma Skin Cancer Development

STEPHAN, SONJA; RÖSL, FRANK; CAO, RUI; VINZON, SABRINA EUGENIA; HASCHE, DANIEL; BRASPENNING-WESCH, ILONA

Sydney

Conferencia; 32nd International Papillomavirus Conference; 2018

BackgroundBesides UV radiation, cutaneous human papillomaviruses (HPVs) are considered as cofactors in multi-step process of non-melanoma skin cancer (NMSC) development. The rodent Mastomys coucha is naturally and persistently infected with the cutaneous papillomavirus MnPV and reflects the situation of HPV infection on patients in many aspects.MethodsWe chronically UVB irradiated animals. Emerging squamous cell carcinomas (SCCs) were characterized in detail.ResultsWe could show that only the cooperation of chronic UVB radiation and MnPV infection leads formation of SCCs. These SCCs were both well-differentiated, supporting productive infections and therefore harboring high amounts of episomal and transcriptionally active MnPV-DNA or dedifferentiated with locally very low amounts or even absent MnPV-DNA, despite seropositivity of the animals against MnPV-L1. The presence of DNA damage markers in MnPV-infected cells indicated the interference with DNA repair, leading to an accumulation of mutations. Notably, like in humans, Trp53 was mutated in most SCCs preferentially at two hot-spot mutations, which completely impaired its transactivation efficiency in functional assays. A correlation between mutated p53 and EMT markers indicated dedifferentiation of SCCs after loss of functional p53. Here, MnPV is no longer required to maintain the malignant phenotype resulting in a loss of viral DNA. This is the first study showing a ?hit-and-run? mechanism for a cutaneous papillomavirus in NMSC development.ConclusionCurrently, we are focusing on the mechanisms of the virus-host interplay. Furthermore, we investigate how chronic UVB irradiation is influencing the seroconversion of the animals and whether recently developed broad protective L2-based vaccines can prevent NMSC formation in this preclinical model.