Cutaneous malignant melanoma (CMM), already notorious for its highly aggressive behavior and its recalcitrance to currently available therapeutics is one of the the fastest increasing cancers in the USA. Recent studies have provided compelling evidence for a significant underlying genetic basis for CMM, as well as an initiating role for sunlight exposure in its etiology. The functional relationship, however, between genes and environment in the pathogenesis of melanoma is virtually unknown. Until now, research on this deadly disease has been badly hampered by the lack of an animal model which adequately recapitulates human disease. We have developed a new transgenic mouse model for UV-induced melanoma which, for the first time, shows an etiology, histopathology and molecular pathogenesis remarkably similar to human CMM. In this proposal, we seek to characterize and further validate this model which shows great promise for melanoma investigations. Preliminary data to date have demonstrated that a single neonatal burning dose of UV exposure is necessary and sufficient to induce highly penetrant cutaneous melanoma, arising in apposition to epidermal elements with a junctional morphology and a molecular pathogenetic profile remarkably reminiscent of human melanoma. Specifically, the UV responsiveness and waveband dependence of this model will be established, the role of critical genetic alterations in the tumor suppressor loci Ink4a and p53 occurring in early lesions and in malignant tumors will be investigated using an in vivo genetic approach, and we propose to establish if UV-induced immune alterations play a fundamental role in the early pathogenesis of disease in this model. We anticipate that these studies will provide the major basis for development of this system for application in the design of preventive strategies and therapeutic interventions and for further investigations of the fundamental biology of cutaneous malignant melanoma.
| Noonan, Frances P; Zaidi, M Raza; Wolnicka-Glubisz, Agnieszka et al. (2012) Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun 3:884 |
| Zaidi, M Raza; Davis, Sean; Noonan, Frances P et al. (2011) Interferon-? links ultraviolet radiation to melanomagenesis in mice. Nature 469:548-53 |
| Wolnicka-Glubisz, Agnieszka; Damsker, Jesse; Constant, Stephanie et al. (2007) Deficient inflammatory response to UV radiation in neonatal mice. J Leukoc Biol 81:1352-61 |
| Wolnicka-Glubisz, Agnieszka; Noonan, Frances P (2006) Neonatal susceptibility to UV induced cutaneous malignant melanoma in a mouse model. Photochem Photobiol Sci 5:254-60 |
| Wolnicka-Glubisz, Agnieszka; King, William; Noonan, Frances P (2005) SCA-1+ cells with an adipocyte phenotype in neonatal mouse skin. J Invest Dermatol 125:383-5 |
| De Fabo, Edward C; Noonan, Frances P; Fears, Thomas et al. (2004) Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res 64:6372-6 |
| Recio, Juan A; Noonan, Frances P; Takayama, Hisashi et al. (2002) Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. Cancer Res 62:6724-30 |
