Identification of Somatic Driver Mutations in a Tpl2-/- Model of Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC), originating from epidermal keratinocytes, is the second-most common form of non-melanoma skin cancer. Mainly caused by cumulative ultraviolet exposure, a recent surge in prevalence has been observed. Coupled with high rates of metastasis, this affliction poses a serious public health threat. Tumor Progression Locus 2 (Tpl2), also known as Cot or MAP3K8, is a serine/threonine kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Implicated in a variety of cell growth and inflammation pathways, Tpl2 activity has been identified in numerous cancers including breast, endometrial, thymomas, lymphomas, lung, Hodgkin’s disease, and nasopharyngeal carcinoma. Previously thought to be solely an oncogene, Dr. DeCicco-Skinner’s laboratory has established a tumor suppressor role for Tpl2 in the context of cSCC. The recent pharmaceutical interest in Tpl2 inhibition as a treatment for rheumatoid arthritis or in chemotherapy displays the need for more research on this gene. The purpose of this thesis was to analyze the underlying genetic mechanisms behind increased cSCC susceptibility in Tpl2-/- mice. This was accomplished through the sequencing and mutational analysis of H-ras, Tp53, and EGFR from Tpl2-/- and wildtype tissue and tumor samples.