Edwige ROY

Regional variation in epidermal susceptibility to ultraviolet induced carcinogenesis reflects proliferative activity of epidermal progenitors

Edwige ROY - Experimental Dermatology Group, The University of Queensland Diamantina Institute (Woolloongabba, Australia)

Invited by Lise BOUSSEMART


Epidermal carcinomas are the most common human malignancies and are linked to ultraviolet (UV) irradiation. Despite our progress in understanding the molecular drivers of common skin cancers, the influence of ultraviolet irradiation on their cell of origin remains uncertain. Oncogenic mutations induce by UV can be found in normal skin suggesting that accumulation of oncogenic mutations is necessary to overcome cell intrinsic mechanisms as well as cell of origin restrictions towards tumour formation. A major determinant for a cell to accumulate mutations relies in its ability to persist long term and to give rise to a large clone of mutant cells. It prompted us to examine interfollicular epidermal (IFE) clone size variation upon UVB irradiation and to ask whether UV induced skin cancer is associated with clone size progression and proliferative potential. A multicolour fate tracing (K14Cre/Er::Rainbow3 mice) was used to evaluate size changes in clones of epidermal cells in response to chronic suberythemal ultraviolet B radiation injury. Upon tamoxifen injection basal keratinocytes were labelled randomly with one of five possible fluorescent protein combinations and the size of different clones could be evaluated at different time points. A bimodal progression of epidermal clones was observed. Epidermal clones expanded more if attached to hair follicles (HF) (P< 0.0001) compared to those not attached that remained of smaller size despite months of UV irradiation.

Although there was globally more epidermal proliferation in the presence of UVB irradiation, proliferating cells were concentrated within 60um of HF openings and clones distant from HF harboured label retaining cells suggesting their relative slow cycling behaviour. Functionally, microdissection of clones attached or not to HF followed by whole exome sequencing did not reveal any difference in mutation load between proliferative and slow-cycling clones. However in a UVB inducible murine BCC model (K14Cre/ER::Ptch1lox/+ mice), although keratin17 expressing groups of epidermal cells reflecting hedgehog pathway activation through loss of the second ptch1 allele were evenly distributed across dorsal skin, they were larger in size if attached to HF. More importantly, when distinguishing dysplastic from invasive (BCC) patches, the latter were more likely to be attached to hair follicles. In conclusions, ultraviolet irradiation results in significant stimulation of epidermal proliferation in proximity of hair follicles resulting in alteration of the cell of origin of BCCs. These findings have major implications for the prevention of skin cancer in photodamaged skin.

>> Friday, October 20, 2017 at 9:30 - IGDR conference room (ground floor of Building 4 / Villejean Campus)

Seminar in English, free entry subject to availability

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