Epithelia provide a protective barrier that exposes them to environmental carcinogens. Cancers of epithelial tissues, called carcinoma, account for 85% of all cancers and 78% of all cancer associated mortality. Epithelia undergo continual proliferation and renewal with hierarchical differentiation dependent upon long lived adult tissue stem cell. Many carcinomas arise from pre-malignant transformation, intraepithelial neoplasia referred to as field cancerisation (FC), which is an area that can give rise to multiple primary cancers. FC is a feature of malignancies involving the head and neck,oesophagus, stomach, lungs, cervix, vulva, bladder, colon, breast, ovary, pancreas, prostate and skin. By studying skin FC in a rare genetic disease, Epidermodysplasia verruciformis, and utilising a mouse model of HPV8 infection, I uncovered a novel keratinocyte stem cell (KSC) basis, driven by ΔNp63 expression, common to all causes of skin FC. I now propose to build on this original finding and utilising an innovative approach to determine the cell signalling pathway involved in expansion of this novel KSC population.
I hypothesise that the common mechanism in skin FC, potentially relevant to FC in other tissues, arises from dysregulation of a signalling pathway that results in a switch from p63 TA to ΔN isoforms resulting in expansion of a KSC population that is susceptible to transformation. I propose to use multiple strategies to: 1)Identify the HPV8 gene that is responsible for ΔNp63 overexpression, 2)Determine which signalling pathway(s) is/are activated in HPV8tg mice, resulting in ΔNp63 overexpression 3)Determine the pathway(s) is/are responsible for ΔNp63 overexpression in human skin FC; and 4)Determine whether immunosuppression promotes SCC formation in HPV8tg mice. I have assembled expert international collaborations and relevant partner organisation to help me in this project, so that I can identify novel therapeutic targets for future drug discovery and development.
Field of science
- /medical and health sciences/medical biotechnology/cells technologies/stem cells
- /social sciences/sociology/demography/mortality
- /medical and health sciences/clinical medicine/oncology/cancer
- /medical and health sciences/clinical medicine/oncology/cancer/breast cancer
- /natural sciences/biological sciences/cell biology/cell signaling
Call for proposal
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