NOTCH1 Signaling Regulates Self-Renewal and Platinum Chemoresistance of Cancer Stem-like Cells in Human Non-Small Cell Lung Cancer

作者：Zhang, Yun; Xu, Wei; Guo, Huiqin; Zhang, Yanmei; He, Yuexi; Lee, Sau Har; Song, Xin; Li, Xiaoyan; Guo, Yongqing; Zhao, Yunlong; Ding, Cheng; Ning, Fei; Ma, Yuanyuan; Lei, Qun-Ying; Hu, Xiaoyu; Li, Shengnan^*; Guo, Wei^*

来源：Cancer Research, 2017, 77(11): 3082-3091.

DOI：10.1158/0008-5472.CAN-16-1633

• BREAST-CANCER
• EXPRESSION
• IDENTIFICATION
• RESISTANCE
• POPULATION
• SURVIVIN
• GROWTH
• ADENOCARCINOMA
• TUMORIGENICITY
• PATHWAY

Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse, and therapeutic resistance, but their specific pathogenic characters in many cancers, including non-small cell lung cancer (NSCLC), have yet to be well defined. Here, we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166(+)CD49f(hi)CD104(-)Lin(-) LCSC present in all human specimens of NSCLC examined, regardless of their histologic subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a gamma-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo. Overall, our results define the pathogenic characters of a cancer stem-like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease.

• 出版日期2017-6-1
• 单位南京医科大学; 昆明医科大学; 北京大学; 中国人民解放军军事医学科学院; 北京协和医学院; 中国医学科学院北京协和医院; 北京市肿瘤防治研究所; 清华大学; 中日友好医院; 复旦大学