Partial epithelial-to-mesenchymal transition is prognostic and associates with Slug in head and neck cancer

Therapy resistance leading to local recurrence and metastases remains highly problematic in head and neck squamous cell carcinomas (HNSCC). Single cell RNA-sequencing defined a partial epithelial-to-mesenchymal transition (p-EMT) signature associated with metastases in HNSCC. However, the prognostic value of the p-EMT signature and potential drivers of p-EMT in HNSCC remain unclear. Here, single sample scoring of molecular phenotypes (Singscoring) served to establish clinical p-EMT-Singscores that were significantly associated with nodal metastases and predicted overall survival in two independent HNSCC cohorts. p-EMT-Singscores correlated most strongly with EMT transcription factor (EMT-TF) Slug. In vitro, Slug promoted p-EMT, enhanced invasion, and resistance to irradiation. In patients, Slug protein levels in tumors predicted disease-free survival and its peripheral expression at the interphase to tumor-microenvironment was significantly increased in recurring patients. Thus, p-EMT represents a novel clinical risk-predictor that impacts on HNSCC patients outcome and is partly controlled by Slug.