Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma

Cancer stem cells (CSCs) represent a subpopulation of tumor cells endowed with self-renewal capacity and are considered as an underlying cause of tumor recurrence and metastasis. The metabolic signatures of CSCs and the mechanisms involved in the regulation of their stem cell-like properties still remain elusive. We utilized nasopharyngeal carcinoma (NPC) CSCs as a model to dissect their metabolic signatures and found that CSCs underwent metabolic shift and mitochondrial resetting distinguished from their differentiated counterparts. In metabolic shift, CSCs showed a greater reliance on glycolysis for energy supply compared with the parental cells. In mitochondrial resetting, the quantity and function of mitochondria of CSCs were modulated by the biogenesis of the organelles, and the round-shaped mitochondria were distributed in a peri-nuclear manner similar to those seen in the stem cells. In addition, we blocked the glycolytic pathway, increased the ROS levels, and depolarized mitochondrial membranes of CSCs, respectively, and examined the effects of these metabolic factors on CSC properties. Intriguingly, the properties of CSCs were curbed when we redirected the quintessential metabolic reprogramming, which indicates that the plasticity of energy metabolism regulated the balance between acquisition and loss of the stemness status. Taken together, we suggest that metabolic reprogramming is critical for CSCs to sustain self-renewal, deter from differentiation and enhance the antioxidant defense mechanism. Characterization of metabolic reprogramming governing CSC properties is paramount to the design of novel therapeutic strategies through metabolic intervention of CSCs.

癌症干细胞（Cancer stem cells, CSCs）是一类具备自我更新能力的肿瘤细胞亚群，被认为是肿瘤复发与转移的潜在诱因。目前，CSCs的代谢特征以及调控其干细胞样特性的相关机制仍有待阐明。本研究以鼻咽癌（nasopharyngeal carcinoma, NPC）来源的CSCs为模型，解析其代谢特征，发现CSCs发生了与分化子代细胞截然不同的代谢转变与线粒体重塑。在代谢转变层面，与亲本细胞相比，CSCs更依赖糖酵解途径获取能量。在线粒体重塑层面，CSCs的线粒体数量与功能受该细胞器的生物发生调控，且其圆形线粒体呈核周分布模式，与干细胞中的线粒体分布特征一致。此外，本研究分别阻断CSCs的糖酵解通路、升高活性氧（reactive oxygen species, ROS）水平以及诱导线粒体膜去极化，并探究这些代谢因素对CSCs干性特性的影响。有趣的是，当我们逆转典型的代谢重编程过程时，CSCs的干性特性受到抑制，这表明能量代谢的可塑性调控了干细胞干性状态的获得与丢失平衡。综上，本研究认为代谢重编程对于CSCs维持自我更新能力、抑制分化进程以及增强抗氧化防御机制至关重要。阐明调控CSCs干性特性的代谢重编程机制，对于通过靶向CSCs的代谢干预开发新型治疗策略具有关键意义。