Sydney Cancer Center - Dermatology Program

Home > Research > Research Groups > Dermatology Program

Dermatology Program

Group Leader:
Professor Wolfgang Weninger
Professor Gary Halliday
Associate Professor Diona Damian
Associate Professor Stephen Lee

Members:
Dr James Guy Lyons
Dr Matthew Bugeja
Dr Fergal Moloney
Dr Kirsten Hammond
Dr Scott Byrne

Research Overview
Tumour cell-host cell interactions are critical determinants for the progression of neoplasms. Of particular importance are cytotoxic T cells, as they may recognise and destroy tumour cells. How T cells navigate within the tumour microenvironment, how they interact with neoplastic cells, as well as their overall contribution to the tumour micromilieu is not well understood. A major Aim of Professor Weninger’s laboratory is to define the cellular and molecular cues responsible for the guidance of tumour infiltrating T cells (TIL) through the tumour stroma, and mediation of their communication with neoplastic cells. The principal hypothesis is that the quality of TIL migration and interactions with target cells determines whether a tumour is destroyed or grows unimpeded. To test this hypothesis, the group makes use of a newly-developed two-photon microscopy model that facilitates visualisation of the behaviour of single cells in real-time within the intricate three-dimensional context of intact tumours. The role of specific adhesion receptors in TIL migration is being studied. Furthermore, the molecular composition of the T cell-tumour cell interface will be determined. Finally, the researcher will determine whether cytotoxic granules are released during TIL-tumour cell interactions. These experiments will provide mechanistic insights into the events leading to tumour cell destruction or tumour immune evasion. Therefore, these studies have important implications for the optimisation of immuno-therapeutic strategies that aim to target cancer.

The major goal of Prof Halliday's research programme is to investigate ultraviolet radiation induced photocarcinogenesis. This is being studied at the molecular, mutagenesis, and immunological levels. We are studying the role of two molecular pathways, chromatin remodelling, and the snail transcription factors in mediating skin cancer development. We are also investigating the roles of different UV wavebands in causing the mutations in skin cancer, and the mechanisms by which this occurs. We are also studying the role of different UV wavebands in suppressing immunity to skin cancer, and the mechanisms by which this occurs. More details of each of these projects are given in the sections below. Associate Professor Diona Damian’s group is investigating the effects of ultraviolet (UV) radiation on skin immunity in humans. Even low-dose UV exposure can profoundly impair the skin’s immune defences, and this “UV-induced immunosuppression” plays an important role in the development of skin cancers. Various studies are currently underway to explore the mechanisms and prevention of UV immunosuppression in humans.

Associate Professor Stephen Lee’s group works on the clinical diagnosis of melanoma, lentigo Maligna & non-Caucasian melanoma, pathogenesis and optimal therapy of atypical as well as the outcomes of NMSC treated by superficially Xray therapy at Concord Dermatology. His group is also studying the cutaneous complications of epidermal growth factor receptor inhibitor.

2006/2007 Highlights
First time visualisation of tumour-infiltrating T cells in real-time.

Demonstrated that initial T cell divisions occur in an asymmetric manner.

PhD student Dr Yasmin Renwick has determined the wavelength dependency (action spectrum) of photo-immunosuppression in humans using an in vivo immune model in humans. Her results demonstrate a peak of immunosuppressive effectiveness in the UVB (300nm), but also a second peak in the long-wave UVA (380nm), which was previously thought to be relatively biologically inert. These results have important implications for sunscreen design and contribute to our understanding of photo-immunosuppression.

Master of Medicine student Dr Eleni Yiasemides has shown that nicotinamide (vitamin B3) is highly protective against UV immunosuppression in humans, when delivered either topically or at high oral doses. Dr Geetha Sivapirabu, who is also completing her Master of Medicine degree, has now shown that nicotinamide is immune protective even at very low daily doses, similar to those used by people taking daily vitamin supplements. Nicotinamide is a safe and inexpensive compound which could be used to reduce skin cancer risk in high-risk patients.

Understanding the mechanisms of UV immunosuppression is important for the development of methods to prevent skin cancers. Postdoctoral Fellow Dr Joohong Park is investigating the effects of nicotinamide on UV-induced immunosuppression, cellular energy and apoptosis pathways.

Stephen Lee was appointed a clinical associate professor of the Chinese University of Hong Kong

Elizabeth Dawes-Higgs was appointed a part-time lecturer in dermatology

Stephen Lee was admitted to the Roll of Fellows of the Australian Medical Association, and continues to be the dermatology representative on the AMA Federal Council and an AMA Director

Stephen Lee was an invited speaker at the Biannual China/Japan joint dermatology meeting in Sept. 2006, the 19th World Diabetes Congress in Dec. 2006 and the Annual Scientific Meeting of the Hong Kong Society of Dermatology and Venereology in June 2007.

Publications 2006/2007
1. Ooi, T., Barnetson, R.St.C., Zhuang, L., McKane, S., Lee, J.H., Slade, H.B. and Halliday, G.M. (2006). Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. British Journal of Dermatology 154: 72-78.

2. Phan, T.A., Halliday, G.M., Barnetson, R.St.C. and Damian, D.L. (2006). Spectral and dose dependence of ultraviolet radiation-induced immunosuppression. Frontiers in Bioscience 11: 394-411.

3. Ishri, R.K., Menzies, S. and Halliday, G.M. (2006). Verapamil induces upregulation of P-glycoprotein expression on human monocyte derived dendritic cells. Immunological Investigations 35: 1-18.

4. Halliday, G.M. (2006). Ultraviolet radiation-induced immunosuppression and the role of antigen presenting cells. In “Low-Dose Radiation Exposures and Bio-Defense System. Proceedings of the International Symposium on Low-Dose Radiation Exposures and Bio-Defense System” Edited by S. Tanaka, K. Fujikawa, Y. Oghiso, Department of Radiobiology, Institute for Environmental Sciences, Japan, pp19-22.

5. Barnetson, R.St.C., Ooi, T.K.T., Zhuang, L.Q., Halliday, G.M., Reid, C.M., Walker, P.C., Humphrey, S.M. and Kleinig, M.J. (2006). [Nle4-D-Phe7]- alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers. Journal of Investigative Dermatology 126(8): 1869-1878.

6. Russo, P.A.J. and Halliday, G.M. (2006). Inhibition of nitric oxide and reactive oxygen species production improves the ability of a sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. British Journal of Dermatology 155: 408-415.

7. Byrne, S.N., Spinks, N. and Halliday, G.M. (2006). The induction of immunity to a protein antigen using an adjuvant is significantly compromised by ultraviolet A radiation. Journal of Photochemistry and Photobiology B: Biology 84: 128-134.

8. Phan, T.A., Halliday, G.M., Barnetson, R.St.C. and Damian, D.L. (2006). Melanin differentially protects from the initiation and progression of threshold UV-induced erythema depending on UV waveband. Photodermatology, Photoimmunology and Photomedicine 22: 174-180.

9. Howes, R.A., Halliday, G.M., and Damian, D.L. (2006) . Effect of topical melatonin on ultraviolet radiation-induced suppression of Mantoux reactions in humans. Photodermatology, Photoimmunology and Photomedicine 22: 267-269.

10. Zhang, G., Luo, X., Sumithran, E., Pua, V.S.C., Barnetson, R.St.C., Halliday, G.M. and Khachigian, L.M. (2006). Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. Oncogene 25 (55): 7260-7266.

11. Howes, R.A., Halliday, G.M., Barnetson, R.St.C., Friedmann, A.C. and Damian, D.L. (2006). Topical capsaicin reduces ultraviolet radiation-induced suppression of Mantoux reactions in humans. Journal of Dermatological Science 44: 113-115.

12. Dixon, K.M., Deo, S.S., Norman, A.W., Bishop, J.E., Halliday, G.M., Reeve, V.E. and Mason, R.S. The vitamin D rapid response pathway is relevant for in vivo photoprotection. Journal of Steroid Biochemistry and Molecular Biology (in press accepted 4/8/06).

13. Gupta, R., Dixon, K.M., Deo, S.S., Holliday, C.J., Slater, M., Halliday, G.M., Reeve, V.E. and Mason, R.S. (2007). Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. Journal of Investigative Dermatology 127: 707-715.

14. Schwarz, T. and Halliday, G.M. (2007). Photoimmunology. In “Photodermatology”. Edited by Henry Lim, Herbert Honigsmann and John Hawk. Informa healthcare, New York, pp 55-74.

15. Halliday, G.M. and Rana, S. (2007). The effects of solar radiation on the immune response in humans. In “Biophysical and physiological effects of solar radiation on human skin”. Edited by Paolo U. Giacomoni. European Society for Photobiology. The Royal Society for Chemistry, pp 127 – 164 (in press, expected to be published November 2007).

16. Moloney, F.J. and Halliday, G.M. (2007). Non-melanoma skin cancer. In “Clinical Immunodermatology”. Edited by Anthony Gaspari and Stephen Tyring. Springer-Verlag, London (Expected to be published 2007).

17. Halliday, G.M. and Rana S. (2008). Waveband and dose dependency of sunlight-induced immunomodulation and cellular changes. Photochemistry and Photobiology (expected to be published March 2008).

18. Min, D., Lyons, J .G., Jia, J., Lo, L. & McLennan, S.V. (2006). Reverse MDPF-labeled gelatin zymography: a rapid real-time method for absolute quantitation of tissue inhibitors of metalloproteinases. Electrophoresis, 27, 357-364.

19. Failes, T.W., Cullinane, C., Diakos, C.I., Yamamoto, N., Lyons, J.G. & Hambley,T.W. (2007). Studies of a cobalt(III) complex of the MMP inhibitor marimastat: a potential hypoxia-activated prodrug. Chemistry, 13, 2974-82.

20. Lavin PG, Laing M E, O’Kelly P, Moloney F. J, Gopinathan D, Al Aradi A, Shields D C, Murphy G M, Conlon P J. Improved Renal Allograft Survival with Vitamin D Receptor Polymorphism. Renal failure. 2007 Oct 29;7(Epub ahead of print)

21. Laing M E, Dicker P, Moloney F. J, Ho W L, Murphy G M, Conlon P, Whitehead A S, Shields D C. Association of methylenetetrahydrofolate reductase polymorphism and the risk of squamous cell carcinoma in renal transplant patients. Transplantation. 2007 Jul 15;84(1):113-116.

22. Moloney F J, Collins P. Randomised, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol. 2007 Jul;157(1):87-91

23. Moloney F. J, Hughes R, O’Shea D, Kirby. Type I immediate hypersensitivity reaction to cyanocobalamin but not hydroxycobalamin. Clin Exp Dermatol. (Accepted for publication)

24. Moloney F. J, Hayden J, Sheahan K, Collins P. Bilateral lower limb erythematous papules with myalgia. Clin Exp Dermatol. 2007 Jul;32(4):475-6.

25. Moloney F. J, Rogers S. Life imitating art. Br J Dermatol. 2007 May;156(5):1086.

26. Matsumura Y*, Byrne S. N*, Nghiem D X, Miyahara Y, Ullrich S E. 2006 A role for inflammatory mediators in the induction of immunoregulatory B cells. Journal of Immunology 177(7) 4810-4817. * Both of these authors contributed equally to this work.

27. Wolf P, Nghiem D X, Walterscheid J P, Byrne S N, Matsumura Y, Matsumura Y, Bucana C, Ananthaswamy H N, Ullrich S E. 2006. Platelet-activating factor (PAF) is crucial in psoralen+UVA (PUVA)-induced immune suppression, inflammation, and apoptosis. American Journal of Pathology 169(3) 795-805.

28. Byrne S. N, Spinks N, Halliday G. M. 2006. The induction of immunity to a protein antigen using an adjuvant is significantly compromised by ultraviolet A radiation Journal of Photochemistry and Photobiology B: Biology 84(2) 128-134

29. Damian D L, Thompson JF. Treatment of extensive cutaneous melanoma metastases with topical diphencyprone. Journal of the American Academy of Dermatology 56:869-71, 2007

30. Dalli, R, Kumar, R, Kennedy, P, Maitz, P, Lee, S, Johnson, R. Toxic epidermal necrolysis/stevens-johnson syndrome: current trends in management. ANZ journal of surgery. 2007; 77: 671-676 [Abstract]

31. Jabbour, J, Cumming, R, Scolyer, R, Hruby, G, Thompson, J, Lee, S. Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease-results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Annals of surgical oncology : the official journal of the Society of Surgical Oncology. 2007; 14: 1943-52 [Abstract]

32. Hui, S, Tang, W, Wong, T, Lau, K, Lee, S, Chong, L, Lo, K. Cutaneous melanoma: a population-based epidemiology report with 989 patients in Hong Kong. Clinical and experimental dermatology. 2007; 32: 265-7 [Abstract]

33. Lee, S. Non-infective skin conditions associated with diabetes. Diabetes Management Journal. June 2007; 19: 6

34. Chang, J.T., V.R. Palanivel, I. Kinjyo, F. Schambach, A.M. Intlekofer, V.P. Zediak, A. Banerjee, Longworth S.A, Vinup K.E, Mrass P, Oliaro J, Killeen N, Orange J.S, Russell S.M, Weninger W, and Reiner S.L. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 2007, 315:1687-91

35. Random migration precedes stable target cell interactions of tumor infiltrating T cells. Mrass P, Takano H, Daxini S, Lasaro M, Iparraguirre A, Cavanagh L.L, von Andrian U.H, Ertl H.C, Haydon P.G, and Weninger W. J Exp Med, 2006, 203:2749-613. Fukunaga M, Martinex G, Liu Z.J, Kalabis J, Mrass P, Weninger W, Planque N, Perbal G, Firth S.M, Baxter RC, Herlyn M. CCN3 controls proliferation and localization of melanocytes in the human epidermis. J Cell Biol, 2006, 175:163-169

36. Mempel T, Pittet M.J, Khazaie, K, Weninger W, Weissleder R, von Boehmer H, von Andrian U.H. Regulatory T cells reversibly suppress CD8 killer cell function independent of effector differentiation, Immunity 2006; 25:129-41.

37. Whitmore M.M., Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams B.R. Negative regulation of TLR-signaling pathways by activating transcription factor-3. J Immunol, 2007, 15;179(6):33622-30.

38. Damian D.L, Patterson C.R.S, Stapelberg M, Park J, Barnetson R. St.C, Halliday G.M. Ultraviolet radiation-induced immmunosuppression is greater in men and prevented by topical nicotinamide. JID, online publication Sep 20 2007.