美国哈佛医学院David T. Scadden团队发现，时序性诱导代谢紊乱可以克服癌症的化疗抗性。2020年8月6日，《细胞-代谢》在线发表了这一成果。

研究人员追踪了患者体内的白血病细胞，确定了化疗后的最大反应时间，获得了持续存在的细胞并进行了无偏倚的代谢组学研究。研究揭示了化疗前生长或化疗复发后阶段不同的代谢产物。持久存在的细胞以独特的方式利用谷氨酰胺，优先为嘧啶和谷胱甘肽的合成提供底物，而不是线粒体三羧酸循环。

值得注意的是，恶性细胞嘧啶的合成也需要特定骨髓基质细胞提供天冬氨酸。针对残留的白血病起始细胞选择性抑制谷氨酰胺代谢或嘧啶合成，可改善白血病小鼠模型和患者来源异种移植物细胞的存活率。研究人员认为细胞内或针对小生境的时序性代谢破坏可以利细胞短暂的脆弱性诱导癌细胞代谢瓦解，这或许可以克服化学耐药问题。

据悉，当恶性细胞克服化疗和周围大量死亡细胞副产物引起的极端代谢瓶颈时，肿瘤就开始复发。在急性髓细胞性白血病患者中病情缓解很常见，但很少可以被治愈。

附：英文原文

tle: Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance

Author: Nick van Gastel, Jessica B. Spinelli, Azeem Sharda, Amir Schajnovitz, Ninib Baryawno, Catherine Rhee, Toshihiko Oki, Eliane Grace, Heather J. Soled, Jelena Milosevic, David B. Sykes, Peggy P. Hsu, Matthew G. Vander Heiden, Charles Vidoudez, Sunia A. Trauger, Marcia C. Haigis, David T. Scadden

Issue&Volume: 2020-08-06

Abstract: Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneckof stress from chemotherapy and the byproducts of the massive cell death in the surroundingregion. 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 persistingcells, and conducted unbiased metabolomics, revealing a metabolite profile distinctfrom the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutaminein a distinctive manner, preferentially fueling pyrimidine and glutathione generation,but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidinesynthesis also required aspartate provided by specific bone marrow stromal cells.Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiatingcells and improved survival in leukemia mouse models and patient-derived xenografts.We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploita transient vulnerability and induce metabolic collapse in cancer cells to overcomechemoresistance.

DOI: 10.1016/j.cmet.2020.07.009

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30367-3