当前位置: X-MOL 学术Cell Metab. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance.
Cell Metabolism ( IF 29.0 ) Pub Date : 2020-08-06 , DOI: 10.1016/j.cmet.2020.07.009
Nick van Gastel 1 , Jessica B Spinelli 2 , Azeem Sharda 1 , Amir Schajnovitz 1 , Ninib Baryawno 3 , Catherine Rhee 1 , Toshihiko Oki 1 , Eliane Grace 1 , Heather J Soled 1 , Jelena Milosevic 4 , David B Sykes 4 , Peggy P Hsu 5 , Matthew G Vander Heiden 6 , Charles Vidoudez 7 , Sunia A Trauger 7 , Marcia C Haigis 2 , David T Scadden 1
Affiliation  

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.



中文翻译:

诱导定时代谢崩溃以克服癌症化学抗性。

当恶性细胞通过化学疗法压力和周围区域大量细胞死亡的副产品的极端代谢瓶颈时,癌症复发就开始了。在急性髓系白血病中,完全缓解很常见,但很少有人治愈。我们在体内追踪白血病细胞,定义了化疗后最大反应的时刻,捕获了持久的细胞,并进行了无偏的代谢组学,揭示了与化疗前生长或化疗后复发阶段不同的代谢物谱。持久细胞以独特的方式使用谷氨酰胺,优先促进嘧啶和谷胱甘肽的产生,而不是线粒体三羧酸循环。值得注意的是,恶性细胞嘧啶合成也需要特定骨髓基质细胞提供的天冬氨酸。针对残留的白血病起始细胞选择钝化谷氨酰胺代谢或嘧啶合成,并提高白血病小鼠模型和患者来源的异种移植物的存活率。

更新日期:2020-09-01
down
wechat
bug