Understanding the distinct metabolic characteristics of cancer stem cells (CSC) may allow us to better cope with the clinical challenges associated with them. In this study, OSCC cell lines (CAL27 and HSC3) and multicellular tumor spheroid (MCTS) models were used to generate CSC-like cells. Quasi-targeted metabolomics and RNA sequencing were used to explore altered metabolites and metabolism-related genes. Pathview was used to display the metabolites and transcriptome data in a KEGG pathway. The single-cell RNA sequencing data of six patients with oral cancer were analyzed to characterize in vivo CSC metabolism. The results showed that 19 metabolites (phosphoethanolamine, carbamoylphosphate, etc.) were upregulated and 109 metabolites (2-aminooctanoic acid, 7-ketocholesterol, etc.) were downregulated in both MCTS cells. Integration pathway analysis revealed altered activity in energy production (glycolysis, citric cycle, fatty acid oxidation), macromolecular synthesis (purine/pyrimidine metabolism, glycerophospholipids metabolism) and redox control (glutathione metabolism). Single-cell RNA sequencing analysis confirmed altered glycolysis, glutathione and glycerophospholipid metabolism in in vivo CSC. We concluded that CSCs are metabolically inactive compared with differentiated cancer cells. Thus, oral CSCs may resist current metabolic-related drugs. Our result may be helpful in developing better therapeutic strategies against CSC.
理解癌症干细胞（CSC）独特的代谢特征，有助于我们更好地应对其带来的临床挑战。本研究利用口腔鳞状细胞癌（OSCC）细胞系（CAL27和HSC3）及多细胞肿瘤球体（MCTS）模型生成CSC样细胞，采用准靶向代谢组学和RNA测序技术探究其代谢物及相关基因的变化，并利用Pathview工具在KEGG通路中展示代谢物与转录组数据。通过分析六例口腔癌患者的单细胞RNA测序数据，进一步解析体内CSC的代谢特征。结果显示，MCTS细胞中有19种代谢物（如磷酸乙醇胺、氨基甲酰磷酸等）表达上调，109种代谢物（如2-氨基辛酸、7-酮胆固醇等）表达下调。整合通路分析表明，其能量生成（糖酵解、柠檬酸循环、脂肪酸氧化）、大分子合成（嘌呤/嘧啶代谢、甘油磷脂代谢）及氧化还原调控（谷胱甘肽代谢）等通路活性发生改变。单细胞RNA测序分析证实，体内CSC的糖酵解、谷胱甘肽及甘油磷脂代谢同样发生显著变化。本研究得出结论：与分化型癌细胞相比，CSC处于代谢相对抑制状态，这可能导致口腔CSC对现有代谢相关药物产生抵抗。该发现或将为开发针对CSC的更有效治疗策略提供理论依据。
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