YAP drives cutaneous squamous cell carcinoma formation and progression
journal contributionposted on 2020-09-14, 10:48 authored by Zoé Vincent-Mistiaen, Ahmed Elbediwy, Hannah Vanyai, Jennifer Cotton, Gordon Stamp, Emma Nye, Bradley Spencer-Dene, Gareth J Thomas, Junhao Mao, Barry Thompson
Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.
Hippo pathwayYAPcarcinomadevelopmental biologymouseregenerative medicinestem cellsAdaptor Proteins, Signal TransducingAnimalsCarcinogenesisCarcinoma, Squamous CellCell NucleusDisease ProgressionEpidermisEpithelial-Mesenchymal TransitionHumansMicePhosphoproteinsSkin NeoplasmsTranscription FactorsZinc Finger E-box-Binding Homeobox 1Thompson FC001180HP0601 Biochemistry and Cell Biology