Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process with strong implications in cancer progression. Understanding the metabolic alterations associated with EMT may open new avenues of treatment and prevention. Here we used 13C carbon analogs of glucose and glutamine to examine differences in their utilization within central carbon and lipid metabolism following EMT in breast epithelial cell lines. We found that there are inherent differences in metabolic profiles before and after EMT. We observed EMT-dependent re-routing of the TCA-cycle, characterized by increased mitochondrial IDH2-mediated reductive carboxylation of glutamine to lipid biosynthesis with a concomitant lowering of glycolytic rates and glutamine-dependent glutathione (GSH) generation. Using weighted correlation network analysis, we identified cancer drugs whose efficacy against the NCI-60 Human Tumor Cell Line panel is significantly associated with GSH abundance and confirmed these in vitro . We report that EMT-linked alterations in GSH synthesis modulate the sensitivity of breast epithelial cells to mTOR inhibitors. Implications: EMT in breast cells causes an increased demand for glutamine for fatty acid biosynthesis, altering its contribution to glutathione biosynthesis, which sensitizes the cells to mTOR inhibitors. This article is featured in Highlights of This Issue, [p. 1439][1] [1]: /lookup/volpage/19/1439?iss=9

中文翻译：

---

EMT 衍生的谷氨酰胺代谢改变使间充质乳腺细胞对 mTOR 抑制敏感

上皮间质转化 (EMT) 是一个基本的发育过程，对癌症进展具有重要意义。了解与 EMT 相关的代谢改变可能会开辟新的治疗和预防途径。在这里，我们使用葡萄糖和谷氨酰胺的 13C 碳类似物来检查它们在乳腺上皮细胞系中 EMT 后中央碳和脂质代谢中的利用差异。我们发现 EMT 前后的代谢特征存在固有差异。我们观察到 TCA 循环的 EMT 依赖性重新路由，其特征是线粒体 IDH2 介导的谷氨酰胺还原羧化作用增加至脂质生物合成，同时降低糖酵解速率和谷氨酰胺依赖性谷胱甘肽 (GSH) 的生成。使用加权相关网络分析，我们确定了抗 NCI-60 人肿瘤细胞系面板的功效与 GSH 丰度显着相关的抗癌药物，并在体外证实了这些。我们报告 GSH 合成中与 EMT 相关的改变调节乳腺上皮细胞对 mTOR 抑制剂的敏感性。启示：乳腺细胞中的 EMT 导致脂肪酸生物合成对谷氨酰胺的需求增加，改变了其对谷胱甘肽生物合成的贡献，从而使细胞对 mTOR 抑制剂敏感。这篇文章被收录在本期的亮点中，[p. 1439][1][1]：/lookup/volpage/19/1439?iss=9 我们报告 GSH 合成中与 EMT 相关的改变调节乳腺上皮细胞对 mTOR 抑制剂的敏感性。启示：乳腺细胞中的 EMT 导致脂肪酸生物合成对谷氨酰胺的需求增加，改变了其对谷胱甘肽生物合成的贡献，从而使细胞对 mTOR 抑制剂敏感。这篇文章被收录在本期的亮点中，[p. 1439][1][1]：/lookup/volpage/19/1439?iss=9 我们报告 GSH 合成中与 EMT 相关的改变调节乳腺上皮细胞对 mTOR 抑制剂的敏感性。启示：乳腺细胞中的 EMT 导致脂肪酸生物合成对谷氨酰胺的需求增加，改变了其对谷胱甘肽生物合成的贡献，从而使细胞对 mTOR 抑制剂敏感。这篇文章被收录在本期的亮点中，[p. 1439][1][1]：/lookup/volpage/19/1439?iss=9