Cancer gene discovery and immunosurveillance studies using Sleeping Beauty mouse models

Cancer is the second leading cause of death in the United States. The majority of cases are caused by sporadic somatic mutation, which leads to cellular transformation over time. Therefore, cancer gene identification is a major focus of current research efforts. Understanding how key driver mutations result in cancer could lead to the design of better targeted therapies. The Sleeping Beauty (SB) transposon system can be used to identify driver mutations in a variety of tumor types. SB mutagenesis mimics the sporadic accumulation of somatic mutations found in spontaneous human cancers. This system also has an additional benefit over chemical carcinogenesis models in that key cancer gene candidates are easily identified with high-throughput sequencing and subsequent bioinformatic analysis. Using SB, our lab recently identified a novel oncogene involved in non-melanoma skin cancer called Zmiz1, the biological function of which is not well studied. A major focus of my thesis work was to characterize Zmiz1 and its role in skin cancer. This gene encodes a protein with predicted E3 SUMO ligase activity. My work has provided the first evidence firmly establishing an oncogenic role for Zmiz1 in cutaneous malignancy, thereby generating a novel transgenic mouse model of skin carcinogenesis. Importantly, we observed tumor-specific overexpression of an endogenous ZMIZ1 isoform in human squamous cell carcinomas. Non-melanoma skin cancer is the most common malignancy worldwide, and it disproportionally affects immunosuppressed patients. One proposed explanation for this is the concept of tumor immunosurveillance, whereby the