Environmental carcinogens, including ultraviolet radiation and polycyclic aromatic hydrocarbon exposures, are major contributors to increasing rates of skin cancer worldwide. In this dissertation, I investigate mechanisms which underlie resistance to skin carcinogenesis, thus advancing our understanding of tumor development and suppression. Previous work has shown that mice deficient in the chromatin remodeling factor High mobility group AT-hook 2 (Hmga2) are highly resistant to ultraviolet-B (UVB) induced melanoma formation, however, the expression of Hmga2 in somatic tissue and its effects on gene expression and phenotype have not been well described. In Chapter 2 of this dissertation, I utilize genetically modified mouse models to show that Hmga2 is expressed in a population of proliferative epidermal stem cells and is required for the normal cutaneous response to UVB including immune cell infiltration, epidermal cell hyperplasia, and melanocyte stem cell activation and migration, as determined through histological analysis. Through mRNA sequencing, these processes are found to be driven by cyclic-AMP (cAMP), thus deepening our understanding of Hmga2 in melanoma suppression.

Chapter 3 builds upon the finding that Hmga2 is expressed in proliferative epidermal stem cells and tests the hypothesis that Hmga2 is required for wound healing and hair cycle progression, two processes driven by epidermal stem cell proliferation. Through rigorous histological sample analysis and full thickness wound models, it is determined that hair cycle aberrations occur with loss of Hmga2, but wound healing is not affected. This study contributes to our understanding of epidermal Hmga2 in the context of homeostasis and injury, in addition to its role in tumorigenesis described in Chapter 2.

Chapter 4 investigates whether complex tissue regeneration is protective against carcinogenesis in a mammalian model capable of extensive skin regeneration, the spiny mouse. Following a prolonged period of DMBA/TPA chemical carcinogenesis, the spiny mouse shows marked resistance to tumor development in a process mediated by p-ERK dependent cell death and tissue remodeling within the epidermal cell compartment which would serve as the tumor cell of origin.

Ultimately, the work presented here advances our knowledge in the fields of skin carcinogenesis, wound healing, and homeostasis through diverse animal models and experimental approaches.