A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) remains among the most aggressive human cancers. Tumor progression and aggressiveness in SCC are largely driven by Tumor Propagating Cells (TPCs). Aerobic glycolysis, also known as the Warburg Effect, represents a characteristic of many cancers, yet 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 (SIRT6) is a robust tumor suppressor in SCC, acting as a modulator of glycolysis in these tumors. 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. Altogether, 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-tumor heterogeneity.

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

“…This would require elevated fatty acid β-oxidation for protection of adrenocortical zona fasciculata cells from ROS. In addition, previous work demonstrated that enhanced glycolysis can combat oxidative stress via increasing glutathione metabolism and maintaining redox balance [68], a potential factor contributing to the larger tumor diameter in APAs with KCNJ5 mutations. Additionally, our data showed an increased antioxidant response via an enhanced unfolding protein response and autophagy [47,48], suggesting that multiple mechanisms participate in the detoxification of ROS and aid adrenocortical tumor cell survival.…”

Metabolic analysis as a driver for discovery, diagnosis, and therapy

“…After the surprising finding that glucosamine constitutes a significant fraction of the monosaccharides composing glycogen in the mouse brain, MALDI MSI revealed that defects in glycogen breakdown resulted in co-localized glycogen accumulation and depletion of N-linked glycans (Sun et al, 2021). In genetic mouse models of squamous cell carcinoma, MALDI MSI provided evidence for a subset of CD34+ cells containing increased glutathione abundance, conferring oxidative stress resistance and tumorigenic potential in vivo (Choi et al, 2021). MALDI MSI has pushed into isotope tracing with recent studies annotating metabolite labeling in regions of the mouse brain (Wang et al, 2022).…”

Lactylation: a Passing Fad or the Future of Posttranslational Modification

“…Dysregulation of histone Kla by lactate disrupts the balance of gene transcription and causes diseases including cancer. Choi et al recently discovered that the absence of NAD+-dependent histone deacetylase sirtuin 6 (SIRT6) enriches tumor-propagating cells (TPCs) by improving lactate production, in turn causing a much more aggressive tumorigenic phenotype in squamous cell carcinoma (SCC) [41]. TPCs regulate survival, recurrence, metastasis, therapeutic resistance, and immune resistance in various malignant tumors.…”