A unique subset of glycolytic tumor propagating cells drives squamous cell carcinoma. A unique subset of glycolytic tumor propagating cells drives squamous cell carcinoma

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. Overall design: We examined 284 tumor propagating cells (TPCs) from two wild type (WT) and two Sirt6-/- mice using the Smart-seq2 protocol for single-cell transcriptomics.

头颈鳞状细胞癌（Head and Neck Squamous Cell Carcinoma，HNSCC）仍是人类最具侵袭性的恶性肿瘤之一。鳞状细胞癌（Squamous Cell Carcinoma，SCC）的肿瘤进展与侵袭性主要由肿瘤增殖细胞（Tumor Propagating Cells，TPCs）驱动。有氧糖酵解，又称瓦伯格效应（Warburg Effect），是诸多癌症的典型代谢特征，但这种代谢适应在鳞状细胞癌中是否具有功能性重要意义，以及其发挥作用的具体阶段，目前仍知之甚少。本研究证实，依赖烟酰胺腺嘌呤二核苷酸（NAD+）的组蛋白去乙酰化酶沉默信息调节因子6（Sirtuin 6，SIRT6）是鳞状细胞癌中强效的肿瘤抑制因子，可调控此类肿瘤的糖酵解过程。值得注意的是，我们发现糖酵解增强并非发生于肿瘤进展的晚期阶段，而是特异性地存在于肿瘤增殖细胞中。更为重要的是，通过对肿瘤增殖细胞开展单细胞RNA测序（single cell RNA sequencing）分析，我们鉴定出一类具有高糖酵解活性、磷酸戊糖途径与谷胱甘肽代谢增强特征的肿瘤增殖细胞亚群，这些特征与更强的抗氧化应答显著相关。综上，本研究揭示糖酵解增强是鳞状细胞癌的核心驱动因素，更为关键的是，我们鉴定出一类肿瘤增殖细胞亚群作为瓦伯格效应的起源细胞，明确了代谢特征是肿瘤内异质性的关键标志。
实验设计概述：我们采用Smart-seq2技术开展单细胞转录组分析，共检测了来自2只野生型（wild type，WT）小鼠与2只Sirt6基因敲除（Sirt6-/-）小鼠的284个肿瘤增殖细胞（TPCs）。