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Simple Summary  Head and neck squamous cell carcinomas (HNSCC) are common malignancies with considerable morbidity and a high death toll worldwide. Resistance towards multi-modal therapy modalities composed of surgery, irradiation, chemo- and immunotherapy represents a major obstacle in the efficient treatment of HNSCC patients. Patients frequently show nodal metastases at the time of diagnosis and endure early relapses, oftentimes in the form of local recurrences. Differentiation programs such as the epithelial-to-mesenchymal transition (EMT) allow individual tumor cells to adopt cellular functions that are central to the development of metastases and treatment resistance. In the present review article, the molecular basis and regulation of EMT and its impact on the progression of HNSCC will be addressed.    Abstract  Head and neck squamous cell carcinomas (HNSCC) are common tumors with a poor overall prognosis. Poor survival is resulting from limited response to multi-modal therapy, high incidence of metastasis, and local recurrence. Treatment includes surgery, radio(chemo)therapy, and targeted therapy specific for EGFR and immune checkpoint inhibition. The understanding of the molecular basis for the poor outcome of HNSCC was improved using multi-OMICs approaches, which revealed a strong degree of inter- and intratumor heterogeneity (ITH) at the level of DNA mutations, transcriptome, and (phospho)proteome. Single-cell RNA-sequencing (scRNA-seq) identified RNA-expression signatures related to cell cycle, cell stress, hypoxia, epithelial differentiation, and a partial epithelial-to-mesenchymal transition (pEMT). The latter signature was correlated to nodal involvement and adverse clinical features. Mechanistically, shifts towards a mesenchymal phenotype equips tumor cells with migratory and invasive capacities and with an enhanced resistance to standard therapy. Hence, gradual variations of EMT as observed in HNSCC represent a potent driver of tumor progression that could open new paths to improve the stratification of patients and to innovate approaches to break therapy resistance. These aspects of molecular heterogeneity will be discussed in the present review.

Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas