Probing the role of aging in basal cell carcinoma development and treatment response

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Relatively young mice are used for most biomedical research studies investigating human disease, even if the disease under study is much more common in aging patients. For example, basal cell carcinoma (BCC) is an extremely common skin cancer strongly associated with aging in humans, and yet mouse models of BCC examining the molecular basis and biology of these tumors routinely use young experimental animals. The goal of this proposal is to determine whether BCCs that develop in aged mice are different than BCCs arising in young mice; specifically, whether the tumors arising in aged mice are a more accurate model of human BCC. The age-related increase in human BCC incidence has been attributed to the gradual accumulation of mutations in genes encoding proteins in the Hedgehog pathway, which is deregulated in essentially all BCCs. However, multiple alterations take place both at the organismal level and in skin during the aging process, raising the possibility that aged skin responds differently than young skin to the same oncogenic signal. To produce BCCs in young as well as old mice, we will use a well-characterized, highly tractable, genetically- inducible mouse model that leads to uncontrolled activation of Hedgehog signaling, the oncogenic driver in BCC. During the first phase (UH2) of this project, we will breed mice to generate a sufficiently large cohort of experimental animals for tumor induction studies, which will be performed once these mice have aged to the equivalent of 55-60 years of age in humans. We will perform pilot studies to establish conditions needed to achieve transgene expression levels comparable to those measured in young mice that are usually used for these studies, and will obtain a preliminary assessment of tumor development in aged mice. During the second phase (UH3), we will perform transgene induction studies in aged as well as young mice and perform a detailed characterization of the resultant tumors. Since our mouse model allows for reversible activation of transgene expression, we will also assess tumor responses to shut-down of oncogenic Hedgehog signaling as an indicator of treatment response. The successful completion of the proposed studies will establish whether aging influences BCC tumor development in a genetic mouse model, and help determine whether the use of older animals provides a more faithful model of this common age-related human cancer. Our findings may have profound implications for the experimental design of studies using mouse models of BCC and potentially other skin cancers, and will provide a foundation for future work aimed at shedding light on how the aging process affects skin tumorigenesis.