Publication date: 3 July 2018
Source:Cell Metabolism, Volume 28, Issue 1
Author(s): Ming Luo, Li Shang, Michael D. Brooks, Evelyn Jiagge, Yongyou Zhu, Johanna M. Buschhaus, Sarah Conley, Melissa A. Fath, April Davis, Elizabeth Gheordunescu, Yongfang Wang, Ramdane Harouaka, Ann Lozier, Daniel Triner, Sean McDermott, Sofia D. Merajver, Gary D. Luker, Douglas R. Spitz, Max S. Wicha
Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.
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Teaser
Luo et al. report that metabolic stressors modulate breast cancer stem cell (BCSC) state dynamics through ROS-mediated activation of the AMPK-HIF1α axis. They further describe the metabolic pathways and vulnerabilities of epithelial- and mesenchymal-like BCSCs and build a conceptual framework to effectively target both BCSC states in PDX and systemic metastasis models of TNBC.https://ift.tt/2u2KwQL
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