期刊
CELL METABOLISM
卷 32, 期 3, 页码 391-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2020.07.009
关键词
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资金
- Alex's Lemonade Stand Foundation
- Tap Cancer Out
- Koch Institute -DF/HCC Bridge Project
- Swedish Research Council
- MIT Center for Precision Cancer Medicine
- Ludwig Center at MIT
- HHMI
- Harvard Stem Cell Institute
- Ludwig Center at Harvard
- Gerald and Darlene Jordan Chair of Medicine at Harvard
- [2T32CA071345-21A1]
- [5R35CA242379]
Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the byproducts of the massive cell death in the surrounding region. In acute myeloid leukemia, complete remissions are common, but few are cured. We tracked leukemia cells in vivo, defined the moment of maximal response following chemotherapy, captured persisting cells, and conducted unbiased metabolomics, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine and glutathione generation, but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiating cells and improved survival in leukemia mouse models and patient-derived xenografts. We propose that timed cell-intrinsic or nichefocused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance.
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