Abstract
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.
Highlights
Squamous cell carcinoma (SCC) is a type of epithelial cancer that is known to originate in the stratified squamous epithelia of the body, such as the skin, cervix, oesophagus, or oral cavity
The spindleshaped tumour cells of spSCC may instead derive from epithelial cells of the epidermis via an epithelial-to-mesenchymal transition (EMT) (Brabletz et al, 2018; Yang and Weinberg, 2008), a process observed to occur in some mouse models of RasG12D-driven skin carcinomas (Latil et al, 2017)
These results suggest that high levels of nuclear YAP and epidermal wounding may be involved in spSCC formation
Summary
Squamous cell carcinoma (SCC) is a type of epithelial cancer that is known to originate in the stratified squamous epithelia of the body, such as the skin, cervix, oesophagus, or oral cavity. Spindle cell carcinoma (spSCC) is a morphologically distinct type of cancer that consists of spindle-shaped nonepithelial cells, yet can occur in the same bodily locations as SCC. The spindleshaped tumour cells of spSCC may instead derive from epithelial cells of the epidermis via an epithelial-to-mesenchymal transition (EMT) (Brabletz et al, 2018; Yang and Weinberg, 2008), a process observed to occur in some mouse models of RasG12D-driven skin carcinomas (Latil et al, 2017). Formation of SCC may occur by an acceleration of the normal YAP-dependent program of basal layer cell proliferation to produce an overgrown epidermis. The molecular basis of SCC progression to spSCC remains poorly understood
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