Journal
CELL METABOLISM
Volume 30, Issue 4, Pages 720-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2019.07.014
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Funding
- Cancer Research UK [FC0010557, C596/A10419, C596/A26855]
- Francis Crick Institute
- UK Medical Research Council [FC0010557]
- Wellcome Trust [FC0010557]
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Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1 alpha)-mediated mitophagy, clearing damaged mitochondria and limiting ROS. However, hypoxia and reduced mitochondrial capacity promote dependence on glycolysis for ATP production that is supported by cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo. Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities.
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