A Wnt-mediated phenotype switch along the epithelial-mesenchymal axis defines resistance and invasion downstream of ionizing radiation in oral squamous carcinoma

Dynamic transitions of tumour cells along the epithelial-mesenchymal axis are important in tumorigenesis, metastasis and therapy resistance. In this study, we have demonstrated a prominent hybrid epithelial-mesenchymal state in monolayers and 3D spheroids of oral squamous cell carcinoma cells. We have further identified a key role for levels of E-cadherin in stratifying the hybrid cells to compartments with varying levels of radiation response and radiation-induced epithelial-mesenchymal transition. The spheroid response to radiation further entailed the generation of a new cell population with low expression levels of E-cadherin, Vimentin positive (ECADLow/Neg-VIMPos) phenotypic signature bearing an enhanced capacity for radiation resistance and invasion. At the molecular level, transcriptome analysis of spheroids in response to radiation showed an initial burst of misregulation within the first 30min that further declined though still highlighting key alterations in gene signatures. Among others, pathway analysis showed an over representation for the Wnt signalling pathway that was further confirmed to be functionally involved in the generation of ECADLow/Neg-VIMPos population, acting upstream of radiation resistance and tumour cell invasion.