{Delta}Np63{gamma}/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in  Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate  the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the Np63 isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of Np63 modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.

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