Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment.
Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment.
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DOI：
10.1016/j.neo.2015.08.005
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Ackerstaff E
中科院分区：
文献类型：
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作者：
Simões RV;Serganova IS;Kruchevsky N;Leftin A;Shestov AA;Thaler HT;Sukenick G;Locasale JW;Blasberg RG;Koutcher JA;Ackerstaff E
癌细胞在肿瘤发生过程中适应其代谢。我们研究了两个同基因乳腺癌细胞系（高转移性4 T1;非转移性67 NR），以确定其葡萄糖和谷氨酰胺代谢的差异，以应对代谢和环境压力。动态磁共振波谱的13 C-同位素显示，4 T1细胞具有较高的糖酵解和三羧酸（TCA）循环流量比67 NR细胞和糖酵解和氧化磷酸化（OXPHOS）之间的切换容易响应不同的细胞外环境。在源自相同原发性乳腺癌的同基因细胞系中，OXPHOS活性随着转移潜能而增加：4 T1> 4 T07和168 FARN（仅局部微转移）> 67 NR。我们观察到在67 NR细胞中（但不在4 T1细胞中）琥珀酸脱氢酶步骤处的受限TCA循环通量，导致琥珀酸积累并阻碍OXPHOS。在四个同基因细胞系，环境应力调节琥珀酸脱氢酶亚基A的表达，根据转移潜力。此外，葡萄糖衍生的乳酸盐的产生在具有较高转移潜力的细胞系中更依赖于谷氨酰胺。这些研究显示4 T1和67 NR乳腺癌细胞之间TCA循环代谢的明显差异。它们表明，形成细胞分裂酶的4 T1细胞比同基因的非转移性67 NR细胞更善于调节其代谢以应对环境应激。我们认为，代谢可塑性和适应性对转移性乳腺癌表型比单独的快速细胞增殖更重要，这可以1）为早期检测这种表型提供新的生物标志物，可能在诊断时，和2）通过靶向线粒体代谢导致转移性乳腺癌的新治疗策略。
Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.