Journal article
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
Cell metabolism, Vol.28(1), pp.69-86.e6
07/03/2018
DOI: 10.1016/j.cmet.2018.06.006
PMCID: PMC6037414
PMID: 29972798
Abstract
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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•E- and M-BCSCs have divergent sensitivities to glycolysis or redox metabolism inhibition•Hypoxic or oxidant stress promotes M to E state transition by activating AMPK-HIF1α•E-BCSCs are more oxidative (OXPHOS) and reliant on NRF2 antioxidant responses•Co-inhibition of glycolysis and TXN and GSH pathways targets both M- and E-BCSCs
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.
Details
- Title: Subtitle
- Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
- Creators
- Ming Luo - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USALi Shang - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAMichael D Brooks - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAEvelyn Jiagge - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAYongyou Zhu - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAJohanna M Buschhaus - Center of Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USASarah Conley - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAMelissa A Fath - Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242, USAApril Davis - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAElizabeth Gheordunescu - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAYongfang Wang - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USARamdane Harouaka - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAAnn Lozier - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USADaniel Triner - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USASean McDermott - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USASofia D Merajver - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USAGary D Luker - Center of Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USADouglas R Spitz - Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242, USAMax S Wicha - Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, MI 48109, USA
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.28(1), pp.69-86.e6
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cmet.2018.06.006
- PMID
- 29972798
- PMCID
- PMC6037414
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: R01 CA101860, R35 CA197585, R01 CA182804, P30 CA086862, R01 CA196018, U01 CA210152; DOI: 10.13039/100001006, name: BCRF
- Language
- English
- Date published
- 07/03/2018
- Academic Unit
- Pathology; Radiation Oncology
- Record Identifier
- 9984047625702771
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