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Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance
Name
nihms-1630126.pdf
Description
Accepted version
Size
2.41 MB
Format
Adobe PDF
Checksum (MD5)
f2535867f0117f0ac33e810c2d4397ff
Author(s)
van Gastel, Nick
Spinelli, Jessica B
Sharda, Azeem
Schajnovitz, Amir
Baryawno, Ninib
Rhee, Catherine
Oki, Toshihiko
Grace, Eliane
Soled, Heather J
Milosevic, Jelena
Date Issued
2020
Journal
Cell Metabolism
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
© 2020 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 niche-focused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance.
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
10.1016/J.CMET.2020.07.009
