A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma
Authors
Jee-Eun Choi, Carlos Sebastian, Christina M. Ferrer, Caroline A. Lewis, Moshe Sade-Feldman, Thomas LaSalle, Anna Gonye, Begona G. C. Lopez, Walid M. Abdelmoula, Michael S. Regan, Murat Cetinbas, Gloria Pascual, Gregory R. Wojtkiewicz, Giorgia G. Silveira, Ruben Boon, Kenneth N. Ross, Itay Tirosh, Srinivas V. Saladi, Leif W. Ellisen, Ruslan I. Sadreyev, Salvador Aznar Benitah, Nathalie Y. R. Agar, Nir Hacohen, Raul Mostoslavsky
Institution
Harvard Medical School, Boston
Country
United States
Year
2021
Journal
Nature Metabolism
Abstract
Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.