Metformin Targets the Metabolic Achilles Heel of Human Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs), which are capable of repopulating the entire heterogeneous cancer cell populations and are highly resistant to standard chemotherapy. Here we demonstrate that metformin selectively ablated pancreatic CSCs as evidenced by diminished expression of pluripotency-associated genes and CSC-associated surface markers. Subsequently, the ability of metformin-treated CSCs to clonally expand in vitro was irreversibly abrogated by inducing apoptosis. In contrast, non-CSCs preferentially responded by cell cycle arrest, but were not eliminated by metformin treatment. Mechanistically, metformin increased reactive oxygen species production in CSC and reduced their mitochondrial transmembrane potential. The subsequent induction of lethal energy crisis in CSCs was independent of AMPK/mTOR. Finally, in primary cancer tissue xenograft models metformin effectively reduced tumor burden and prevented disease progression; if combined with a stroma-targeting smoothened inhibitor for enhanced tissue penetration, while gemcitabine actually appeared dispensable.胰腺导管腺癌（pancreatic ductal adenocarcinomas）中存在仅具有致瘤性的癌症干细胞（cancer stem cells, CSCs）亚群，这类细胞能够重构整个异质性癌细胞群体，且对标准化疗方案具有高度抗性。本研究证实，二甲双胍可选择性清除胰腺CSCs，具体表现为多能性相关基因及CSCs相关表面标志物的表达水平显著下调。经二甲双胍处理的CSCs，其体外克隆扩增能力因诱导凋亡而被不可逆地阻断。与之相对，非CSCs主要表现为细胞周期阻滞，并未因二甲双胍处理而被清除。从机制层面而言，二甲双胍可上调CSCs内活性氧（reactive oxygen species, ROS）的产生水平，并降低其线粒体跨膜电位。随后在CSCs中诱导产生的致死性能量危机并不依赖AMPK/mTOR通路。最终，在原代癌组织异种移植模型中，二甲双胍可有效降低肿瘤负荷并阻止疾病进展；若联合靶向肿瘤基质的smoothened抑制剂以增强组织穿透性，则吉西他滨（gemcitabine）实际上并非必需。