通过代谢干预杀灭肿瘤干细胞样细胞克服耐药的基础研究

The persistence of cancer stem cells poses a major challenge to cancer treatment. Currently, the metabolic features of cancer stem cells, the underlying regulatory mechanisms, and their links to drug sensitivity remain elusive. Our recent studies suggest that stem-like cancer cells (SP cells) seem to have high glycolytic activity, and their stemness is closely regulated by glucose in the tumor microenviroment. We also found that a small chemical compound MET-709 was able to inhibit cellular energy metabolism and potently eliminate SP cells. Based on these new findings, we propose to compare the metabolic properties of SP and non-SP cells and their drug-resistant variants to reveal the metabolic characteristics of SP cells and their key regulatory mechanisms, to identify the key molecular target of MET-709, and to validate the ability of MET-709 to kill cancer stem cells in vivo. We wil also design mechanism-based drug combination strategies to eliminate cancer cells, aiming at completely eliminate the tumor at its roots. The successful implementation of this research project will significantly advance our understanding of cancer stem cell biology at metabolic level, and will provide a solid basis for developing strategies to improve therapeutic activity and overcome drug resistance.

肿瘤干细胞（CSCs）的存在是肿瘤治疗面临的重大挑战。目前对CSCs代谢特征及其赖以生存的关键代谢环节和与药物敏感性的联系机制尚不清楚。我们前期研究发现，肿瘤干细胞样细胞（SP cells）糖酵解代谢活跃，其干性明显受微环境中葡萄糖的调控。我们进一步发现小分子化合物MET-709能抑制细胞能量代谢，并有效杀灭SP细胞。基于该最新发现，本项目拟通过比较SP和non-SP细胞及其抗药细胞株的基因表达和代谢状况的改变，揭示SP细胞的代谢特征及其重要调控环节，寻找MET-709杀灭CSCs的关键靶点，并验证MET-709在体内杀灭CSCs的疗效；基于MET-709的作用机理，进一步设计该药与传统化疗药物联合应用以期彻底杀灭肿瘤细胞，达到根除肿瘤的目的。该项目的成功实施将从代谢角度大幅度提升我们对CSCs生物学特性的认识，为提高肿瘤治疗疗效和克服耐药提供理论基础和实验依据。

肿瘤干细胞（Cancer stem cells,CSCs）在肿瘤的形成、生长和转移过程中起关键作用，是肿瘤耐药、复发的重要根源。因此，有效清除肿瘤干细胞是肿瘤治疗的关键。本研究从生化代谢的角度揭示了微环境代谢物对于肿瘤干细胞起着显著调节作用，并筛选和鉴定了抗风湿药物金诺芬可通过抑制糖酵解及诱导ROS升高双重机制有效杀灭肿瘤干细胞样侧群细胞，抑制肿瘤克隆形成能力，降低成瘤率；金诺芬与传统化疗药物联合可有效杀灭肿瘤细胞；在研究微环境代谢物对肿瘤干细胞的影响的过程中，我们还意外发现，谷氨酰胺可通过影响β-catenin而调节的氧化还原通路来调节肿瘤干细胞，抑制谷氨酰胺的代谢可以有效消除肿瘤干细胞，增强传统治疗的敏感性，提高肿瘤治疗疗效。该项目的科学产出包括在国际专业主流杂志发表SCI论文8篇，并且以此为基础成功申请获得广州市科技计划项目-一般项目。该研究进一步加深了我们对肿瘤干细胞生物学特性的认识，并为提高肿瘤治疗效果和预防复发提供理论基础和实验数据，具有重要的学术意义和应用价值。