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Skin Biology & Translational Dermatology

Background

The Investigative and Translational Dermatology (ITD) Group (directed by Professor Leigh) was formed in 2007 following the transfer of the Cancer Research UK Skin Tumour Laboratory (CR-UK STL) from London when Professor Leigh was appointed Head of the College of Medicine, Dentistry and Nursing. ITD has now extended to include basic scientists and academic clinicians. The ITD group pursues two over-arching goals: dissecting basic mechanisms implicated in the control of normal skin functioning and underlying the pathogenesis of skin disorders; and, secondly, translating these findings into clinical practice.

Key research themes

Research strategy and goals for the next five years

Overall strategic positioning

The group is currently dependent on CR-UK and Debra programme grants (Leigh) and renewal of this grant funding will be a key priority over the next 2 years. Thus there will be a continuing emphasis on cancer-genetics and translational epithelial tumour biology. Genetic disease studies will continue to contribute to the identification of novel genes causing genodermatoses but will extend into the development of therapeutic agents for disease correction in collaboration with Irwin McLean and Birgit Lane’s groups. The new recruits in epithelial biology (Panteleyev) and inflammatory skin disease (Foerster) will continue to study epidermal signalling pathways

Cancer

Non-melanoma skin cancer

(Proby)

This translational clinical skin cancer programme aims by genetic and epigenetic profiling of cutaneous SCC to elucidate molecular mechanisms involved in the progression from sun-damaged skin to invasive cancers. Over the next 5 years clinically relevant biomarkers and potential therapeutic targets will be identified and give rise to therapeutic strategies aimed at reducing skin cancers in high-risk patients. Collaborations with Albena Dinkova-Kostova (chemoprevention through topical induction of anti-oxidants) and (targeting the immune response) are planned.

The clinical skin cancer programme aims to use genetic and epigenetic profiling to elucidate molecular mechanisms in the progression from sun-damaged skin to invasive keratinocyte skin cancers. We aim to identify clinically relevant biomarkers and potential therapeutic targets and to develop therapeutic strategies aimed at reducing skin cancers in high-risk patients.

Skin Cancer in Recessive Dystrophic Epidermolysis Bullosa RDEB

(South)

RDEB patients have a high life time risk of aggressive skin cancers.Through collaboration with clinicians from UK, Europe, South America and Australia we have established the largest collection of EB SCC material worldwide, which will be curated for Debra. Combining genetic profiling with functional assays of cancer cell behaviour has defined inherent differences between EB and non-EB, UV induced SCC. Future studies will pursue preliminary findings concerning tumour-stromal matrix interactions and the role of basement membrane proteins in tumour formation.

Epidermal biology and Genetics

Ex vivo gene therapy for genetic skin disease

As part of an established European consortium, the group will continue to develop ex vivo gene therapy and cell therapy for RDEB (type VII collagen deficiency).

Desmosomal diseases

The group will build on a track record of identifying and exploring the functional consequences of mutations in human desmosomal genes which cause diseases affecting either skin or heart or both tissues. There will be further research on the biological role of different isoforms of desmosomal proteins and the tissue specificity of desmosomal gene expression involved in skin and heart disease through functional assays of cellular adhesion and the reconstitution of cell-cell junctions.

Epidermal development and epidermal stem cell biology

(Panteleyev): This research aims to identify molecular mechanisms implicated in control of adaptive processes in the skin, such as epidermal barrier formation, desquamation, skin angiogenesis, wound healing, and maintenance of skin stem cells.

Studies aim to understand how deregulation of these mechanisms by environmental stress factors (UV light, hypoxia, and organic toxicants) and to link this to susceptibility of epithelial cells to tumorigenic transformation and malignancy. Using genetically engineered mouse models and state of the art molecular approaches the group is currently dissecting the role of PAS proteins (Hypoxia-induced factors, AhR and ARNT) in modulation of epidermal regulatory pathways through both genetic and epigenetic mechanisms.

Epidermal responses to environmental stressors and its role in tumour formation and prevention

Major goals are:

1. To characterize epidermal responses to ultraviolet radiation and their alterations during conditions mimicking immunosuppressive therapy using cell culture and transgenic mouse models;
2. To develop strategies for protection against ultraviolet radiation–induced skin cancer development under both normal and immunosuppressive conditions;

3. To develop new mechanism-based inhibitors for reduction of the risk for skin cancer in both immune-competent and immune-suppressed human populations.

Inflammatory skin diseases

1. In-depth characterisation of the role of the transcription factor PPARd for inflammatory skin diseases,
2. Validation of a transgenic mouse model suitable for drug screening in psoriasis,
3. Identification and in vivo validation of novel drug targets for the treatment of psoriasis,
4. Studying the role of the molecule Wnt5a in inflammation, cell migration, and invasion, in psoriasis, skin cancer, and melanoma.

Placement of the ITD group within the University:

The ITD has a number of key collaborations across the University

• Cancer Research UK Centre. The group will be founder members of the Dundee Cancer Centre in collaboration with Alistair Thompson, Birgit and David Lane.
• Biomedical Research Institute. Collaboration with Albena Dinkova-Kostova on UV photoprotecton and (Foerster) on mouse models of inflammatory disease (PPARg mice).
• Division Molecular Medicine. Genetics research has had long-standing ties with Professors Birgit Lane, and Irwin McLean, (since 1981) which will continue.
• Clinical collaborative research activities involves the clinical department of dermatology, including work on melanoma with Dr. Colin Fleming, and psoriasis (Dr Sally Ibbotson and Professor Jimmy Ferguson).
• is closely linked to immunologists working at the CMDN, and the Tayside Immunology Group including immunologists from the CLS.

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