Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; [email protected] Department of Surgery, Montreal Common Hospital, McGill University, Montreal, QC H3G 1A4, Canada; veena.sangwan@gmail (V.S.); [email protected] (L.F.) Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Health-related Center, New York, NY 10032, USA Department of Pathology Cell Biology, Division of Oral Maxillofacial Pathology, Columbia University Irving Healthcare Center, New York, NY 10032, USA Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; [email protected] Case Comprehensive Cancer Center, Division of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; [email protected] Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Irving Health-related Center, New York, NY 10032, USA BACE2 Molecular Weight Correspondence: [email protected]; Tel.: +1-212-851-4868 Co-first authors.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This short article is an open access article distributed below the terms and conditions in the Inventive Commons Attribution (CC BY) license ( creativecommons.org/licenses/by/ four.0/).Abstract: Background: Alcohol (ethanol) consumption is often a major risk element for head and neck and esophageal squamous cell carcinomas (SCCs). Even so, how ethanol (EtOH) impacts SCC homeostasis is incompletely understood. Techniques: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations like putative cancer stem cells defined by high CD44 expression (CD44H cells). Final results: Utilizing 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we discovered that EtOH is metabolized by means of alcohol dehydrogenases to induce oxidative strain connected with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis in the majority of SCC cells within organoids. Nevertheless, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy elevated EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor development, and organoid formation rate. Conclusions: This study supplies mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a prospective therapeutic target for the treatment of EtOH-associated SCC. Key phrases: alcohol; autophagy; CD44; organoids; squamous cell carcinomaBiomolecules 2021, 11, 1479. doi.org/10.3390/5-LOX Synonyms biommdpi/journal/biomoleculesBiomolecules 2021, 11,2 of1. Introduction Chronic alcohol consumption poses increased dangers for many cancer sorts [1]. The foremost organ web sites linked to a powerful alcohol-related cancer risk would be the mouth, tongue, throat and also the esophagus [2,3] where squamous cell carcinoma (SCC) represents the main tumor variety. SCC from the head and neck (HNSCC) and also the esophagus (ESCC) are common worldwide, and are deadly resulting from late diagnosis, metastasis, therapy resistance, and early recurrence [4,5]. HNSCC and ESCC develop around the mucosal surface that is directly exposed to higher concentra
