Journal
CELL METABOLISM
Volume 28, Issue 1, Pages 69-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.06.006
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Funding
- NIH [R01 CA101860, R35 CA197585]
- BCRF
- [R01 CA182804]
- [P30 CA086862]
- [R01 CA196018]
- [U01 CA210152]
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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-HIF1 alpha 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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