Vincent-Mistiaen, Zoé I.; (2020) The role of YAP in epidermal homeostasis and tumourigenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The skin epidermis, a stratified squamous epithelium, is the main interface between the body and environment. A pool of resident progenitor keratinocytes continually renews this epithelium to maintain homeostasis in the face of constant physical, chemical and biological attacks. Furthermore, plasticity in the activity of these progenitor cells enables rapid wound healing to maintain barrier function. This flexibility is a double-edged sword, as many of the processes necessary for epithelial tissue repair are implicated in tumourigenesis. Indeed, epidermal carcinomas are the most common cancers worldwide, with incidence continuing to rise. The molecular mechanisms regulating epidermal progenitor cell fate, wound healing and tumour formation are not well understood. In this thesis, I highlight the central role of the transcriptional regulator YAP in these processes. I show that in normal skin, YAP is nuclear and transcriptionally active in basal layer progenitor cells and that this depends on contact with the basement membrane and consequent integrin-Src signalling. Thus, YAP couples progenitor cell adhesion to the basal extracellular matrix with the expression of genes involved in epidermal cell proliferation and hence skin renewal. I also show that nuclear YAP is elevated at the margin of healing wounds, where it stimulates proliferation; in the absence of YAP and its paralogue TAZ, cutaneous wound healing is impaired. However, pathological activation of YAP causes hyperproliferation of these basal layer cells, which can result in epidermal hyperplasia and squamous cell carcinoma (SCC). Indeed, YAP is widely expressed in human SCCs and overexpression of YAP drives SCC in mice. SCC can sometimes progress to a malignant metastatic subtype, characterised by atypical spindle-shaped mesenchymal cells, known as spindle cell SCC (spSCC). I find that whilst human spSCC is characterised by strongly nuclear YAP, epidermal-specific overexpression of activated YAP (NLSYAP- 5SA) in mice does not always cause spSCC, suggesting that another factor could be at play. It is thought that spSCC formation involves an epithelialmesenchymal transition (EMT), but the molecular mechanism is not understood. I noted that whilst SCCs can arise randomly throughout the skin, spSCCs develop at scratch wound sites. I report that EMT transcription factor ZEB1 is widely expressed in human and murine spSCCs, but not in SCCs. During normal wound healing YAP induces transient ZEB1 expression, whereas in the presence of constitutively active YAP, ZEB1 expression is sustained and a YAP-ZEB1 positive feedback loop drives spSCC formation. I propose that YAP synergises with the wound healing response to promote ZEB1-mediated EMT and metaplastic transformation of SCC to spSCC. Thus, YAP provides a link between epithelial damage and tissue repair, which can be hijacked by cancer. This could explain why spSCCs are so frequently associated with skin damage from trauma or UV radiation.

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