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Partial epithelial‐to‐mesenchymal transition (pEMT) contributes to cellular heterogeneity that is associated with nodal metastases and unfavorable clinical parameters in head and neck squamous cell carcinomas (HNSCCs). We developed a single‐cell RNA sequencing signature‐based pEMT quantification through cell type‐dependent deconvolution of bulk RNA sequencing and microarray data combined with single‐sample scoring of molecular phenotypes (Singscoring). Clinical pEMT‐Singscores served as molecular classifiers in multivariable Cox proportional hazard models and high scores prognosticated poor overall survival and reduced response to irradiation as independent parameters in large HNSCC cohorts [The Cancer Genome Atlas (TCGA), MD Anderson Cancer Centre (MDACC), Fred Hutchinson Cancer Research Center (FHCRC)]. Differentially expressed genes confirmed enhanced cell motility and reduced oxidative phosphorylation and epithelial differentiation in pEMThigh patients. In patients and cell lines, the EMT transcription factor SLUG correlated most strongly with pEMT‐Singscores and promoted pEMT, enhanced invasion, and resistance to irradiation in vitro. SLUG protein levels in HNSCC predicted disease‐free survival, and its peripheral expression at the interphase to the tumor microenvironment was significantly increased in relapsing patients. Hence, pEMT‐Singscores represent a novel risk predictor for HNSCC stratification regarding clinical outcome and therapy response that is partly controlled by SLUG. [ABSTRACT FROM AUTHOR]

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. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Fat grafts obtained from a minimal invasive liposuction device contain multipotent stem cells termed adipose-derived stem/stromal cells (ASCs). ASCs can be used for their proposed wound healing relevant characteristics, including for tissue defects in cancer patients. For head and neck cancers, little is known about the effects of ASCs on tumor cells. Using supernatants of ASCs from five patients in different functional experiments, this study aimed to investigate how ASCs influence tumor growth, invasive properties, and neoangiogenesis. The data show that all mentioned characteristics are promoted by fat graft stem cells in vitro in head and neck cancer cell lines. Although clinical relevance of these in vitro findings is unclear, due to the lack of in vivo and clinical data, fat grafts should be used cautiously and complete removal of tumor should be ensured before augmentation in head and neck cancer patients is performed. Human adipose-derived stem/stromal cells (ASCs) are increasingly used as auto-transplants in regenerative medicine to restore tissue defects or induce wound healing, especially in cancer patients. The impact of ASCs on squamous cell carcinoma of the upper aerodigestive tract (UAT) including head and neck and esophageal squamous cell carcinoma (HNSCC and ESCC) is not yet fully understood. ASCs were cultured from subcutaneous, abdominal lipoaspirates of five patients, who received auto-transplants to the head and neck. Supernatants were tested for paracrine effects in functional in vitro assays of proliferation of HNSCC tumor cell line FaDu and ESCC cell line Kyse30, and their cell migration/invasion capacities in Boyden chambers, in addition to endothelial tube formation assay using human umbilical vein endothelial cells (HUVECs). All ASC-derived supernatants enhanced proliferation of FaDu cells, invasive migration, and tube formation by HUVECs, compared to controls. Of five patients' lipoaspirates, ASC-derived supernatants of four patients increased proliferation and invasive migration in Kyse30 cells. The data suggests that ASCs can promote tumor cell proliferation, invasiveness, and neo-angiogenesis in these tumor cell lines of the UAT and HUVEC in a paracrine manner. Although clinical studies on the subject of oncological safety are still needed, these findings emphasize the importance of complete tumor removal before ASCs are used in the head and neck. [ABSTRACT FROM AUTHOR]