Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.

了解癌细胞转移的机制对于预防癌症进展至关重要。在这里，我们研究女性乳腺癌转移起始细胞（MIC）的代谢适应以及这些适应如何塑造其转移表型。我们发现内源性 MIC 取决于氧化三羧酸循环和脂肪酸的使用。仅根据线粒体膜电位或脂质储存对肿瘤细胞进行分类足以识别 MIC。我们进一步确定线粒体产生的柠檬酸被输出到细胞质以产生乙酰辅酶A，这对于维持 MIC 中 H3K27ac 的高水平至关重要。阻断乙酰辅酶A生成途径或H3K27ac特异性表观遗传写入器和读取器会降低上皮间质相关基因的表达、MIC频率和转移潜力。外源性补充短链羧酸、乙酸盐可增加 MIC 频率和转移。在患者队列中，我们观察到氧化磷酸化相关基因的较高表达与远处无复发生存率降低相关。这些数据表明，MIC 特异性且精确地改变其代谢，以有效地定植远处器官。