In vivo mouse models of virus-induced skin cancer, namely keratinocyte carcinoma and Merkel cell carcinoma

In this PhD thesis, two projects both aimed at understanding the molecular mechanisms underlying virus-induced tumour formation and progression in the skin were included. Specifically, two models of skin cancer were used: i) beta Human Papillomavirus (B-HPV) infection and keratinocyte carcinoma (KC); and ii) Merkel Cell Polyomavirus infection and Merkel Cell Carcinoma (MCC). Many evidences suggest a carcinogenic role of B-HPV in KC, especially in the immunosuppressed setting. HPV-associated cutaneous KC occurs mainly in sun-exposed areas of the body, and therefore these viruses are thought to cooperate with UV rays to induce cancer. Here, we used a new mouse model of immunosuppression, obtained by crossing the B-HPV8 transgenic mice with Rag2 deficient mice, to show a functional link between cutaneous PV VIIEIISIUm rerse so 0066 2010 1000 infection, immunosuppression, UVB exposure, and KC development. Our findings clearly demonstrate the concerted contribution of these factors in the accelerated development of skin cancer in an immunosuppressed setting. Within Polyomaviruses, MCPUV is the only family member proven to induce cancer, as it has been associated with the development of MCC. Recently, many studies have highlighted the contribution of tumor microenvironment (TME) in cancer progression suggesting the tumor-promoting role of cancer associated fibroblasts (CAFs) in many cancer types, but data describing CAFs and their molecular function in MCC are still missing. To define the role of CAFs in MCC cancerization, we have isolated CAFs from MCC patients and performed a set of in vivo experiments by injecting patient-derived CAFs along with the MCPVV positive MCC cell line MKL-1 in SCID mice. The results obtained with xenografts indicate a pivotal role for the TME, particularly CAFs in tumour development and metastasis formation