Skin Carcinogenesis

Funding
Collaborators
Key Publications
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Lab Head: Dr Graeme Walker

Our laboratory is interested in the interaction of genetic and environmental factors in melanoma development. How ultraviolet radiation (UVR) initiates melanoma is a hotly debated subject. At present the common mechanistic explanation for melanoma genesis after sun exposure involves genotoxic damage to melanocytes that is not properly repaired. Whether this is true or not may depend upon the context, and in all likelihood the situation is more complex. There are various types of UVR-induced cellular damage, and it is largely unclear which of these is the most important in melanoma induction. In addition, many of the genes involved in melanoma susceptibility and progression are already known, but precisely how their abnormal function results in melanocyte transformation is not understood. We are studying mechanisms of melanoma development in transgenic mice carrying mutations in these genes, investigating whether variation in melanoma susceptibility after sun exposure may depend upon innate differences in pigmentation characteristics, DNA repair capability, and/or other factors that may restrain the proliferation of a mutated melanocyte. One special factor we are focussing on is variation in the proliferative response of melanocytes to UVR, a process inextricably linked to tanning. An increase in melanocyte number is known to be part of a protective response to sun exposure, but it is possible that it can be dangerous if over-activated. It is hoped that this research will provide factual information to help define safe individual levels of sun exposure to minimise the risk of melanoma, and for the development of targeted prevention and treatment strategies. Projects include: 1. Interaction of Mc1r with the pRb and p53 pathways in UVR-induced melanoma development Evidence suggests that there are two principal mechanism of UVR-induced melanoma development. Understanding why this is so is critical, because a given prevention and treatment strategy developed for one group may be useless for another. Genes involved in human melanoma susceptibility (CDK4, ARF, MC1R) may influence one, and not the other mechanism. We are studying how UVR-induced damage may initiate melanoma via different mechanisms. 2. Role of Kit signalling in melanoma and the melanocyte proliferative response to UVR Here the aim is to study how c-Kit signalling, which is induced after UVR exposure, may (a) activate melanoma stem cells (b) enhance DNA repair capability, and (c) act as a promoter of melanoma tumorigenesis. 3. Molecular mechanisms of the delayed tanning response Melanocytes display proliferative and chemotactic responses to UVR exposure that are inextricably linked to tanning. Here we are using pharmacological and other molecular tools to elucidate the signalling pathways involved in these responses. Staff Laboratory Head: Dr Graeme Walker Senior Research Officer: Herlina Handoko Research Assistant: Blake Ferguson To see staff contact details, please type name below and hit Enter Name:

Schematic representation of the positioning of a melanocyte in the epidermal layer of the skin. After UVR exposure, surrounding epidermal keratinocytes release molecules that regulate melanocyte behaviour via their effects on the intracellular pathways shown. Mutation of any component of this signalling network can alter the melanocytes’ response to UVR and potentially increase melanoma risk. A. Arrows denote melanocytes (red) stained an anti-Trp1 antibody. UVR-activated melanocytes (arrowed) can be seen at the base of the epidermis and in the upper portion of a hair follicle. B. Atypical melanocytes in a melanoma.

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Funding

• Cancer Council Queensland
• National Health and Medical Research Council of Australia

Collaborators

• Dr Neil Box, Dept Dermatology, University of Colorado, CO, USA.
• Dr Marianne Broome-Powell, Stanford University, California, USA.
• Dr Brian Gabrielli, Diamantina Institute, University of Queensland.
• Dr Takahiro Kunisada, Gifu University, Japan.
• Professor Konrad Muller, Dept Pathology, University of Tasmania.
• Dr Ian Tonks, QIMR Transgenics laboratory, Brisbane.
• Dr Greg Woods, Menzies Institute, Hobart

Key Publications

Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward NK and Dracopoli NC. (1996). Germline mutations of the p16 binding domain of CDK4 in familial melanoma. Nature Genet, 12:97-99.

Walker GJ and Hayward NK. (2002). Pathways to melanoma development: lessons from the mouse. J Invest Dermatol. 119:783-792 (Invited review).

Walker G, Indsto J, Sood, R, Faruque M, Hu P, Pollock P, Duray P, Holland E, Brown K, Trent J, Mann G, Hayward N. (2004). Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumour suppressor localized to a 9 Mb interval. Genes Chrom Cancer. 41: 56-64.

Hacker E, Irwin N, Muller K, Broome-Powell M, Kay G, Hayward N, and Walker G. (2005). Neonatal ultraviolet radiation exposure is critical for malignant melanoma induction in pigmented Tpras transgenic mice. J Invest Dermatol. 125:1074-7.

Hacker E, Muller K, Gabrielli B, Lincon D, Pavey S, Broome-Powell M, Malumbres M, Barbacid M, Hayward N, and Walker G. (2006). Spontaneous and UVR-induced multiple metastatic melanoma in Cdk4R24C/R24C/TPras mice. Cancer Res. 66:2946-52.

Hacker E, Muller HK, Whiteman D, Pavey S, Hayward N and Walker G. (2008). Decreased expression of IL-18 in the pathway to ultraviolet radiation induced melanoma. Int J Cancer. 123:227-31.

Walker G. (2008). Cutaneous melanoma: how does ultraviolet light contribute to melanocyte transformation? Future Oncology 4:841-56. (Invited review).

Walker G and Box N (2008). Centrality of keratinocyte p53 activation melanocyte localisation within the skin, and tanning response. Expert Rev Dermatol. 3:649-656 (Invited commentary).

Walker G, Kimlin M, Hacker E, Ravishankar S, Muller HK, Beermann F, Hayward N. (2009). Murine neonatal melanocytes exhibit a heightened proliferative response to ultraviolet radiation and migrate to the epidermal basal layer. J Invest Dermatol. 129:184-93.

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