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. Computer simulations supported a model where epidermal populations distant from HF contained committed epidermal progenitors that were quiescent and behaved differently in proximity of HFs to local proliferative signals.
In normal skin or after UVB exposure, the epidermis surrounding HFs was not systematically connected with the deep HF epidermal cells and labelling of Keratin15 expressing cells did not result in labelled cells in the interfollicular epidermis upon chronic UVB irradiation. Long term UVB irradiation resulted in slow cycling progenitors accumulate DNA damage.
In conclusions, this dual behavior of epidermal clones suggests an accumulation of mutations due to UV irradiation distant from the epidermal adnexae with a new understanding of epidermal carcinogenesis.