Epidermal cancers are the most prevalent form of malignancy and are strongly linked to ultraviolet exposure. Although significant progress has been made in our understanding of skin cancer, its origin is to date unclear. It is not understood how photodamaged skin, actinic keratosis and SCCs can harbour the same mutations. In this project, using unique Rainbow mouse genetics technology, we aim to show how different clones of epidermal cells respond to ultraviolet radiation injury and progress. This allowed to track the fate of individual epidermal cells over long periods of chronic ultraviolet exposure. 
Our findings highlight a bimodal progression of epidermal clones. 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 hair follicle openings and clones distant from hair follicles harboured label retaining cells suggesting their relative slow cycling behaviour. Functionally, microdissection of clones attached or not to hair follicles 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 hair follicles. Invasive BCCs emanated from hair follicle attached clones. In conclusions, this dual behaviour of epidermal clones suggests that HF-attached clones in general larger in size and more likely to be affected by a second mutation removing the requirements of the cell of origin with a new understanding of epidermal carcinogenesis.

Epidermal clonal expansion upon UV irradiation: consequences of the epidermal duality of proliferative behaviour on the skin carcinogenesis.