A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program

Several studies have identified a specific metabolic program that is associated with the process of epithelial-mesenchymal transition (EMT). Whereas much is known about the association between glucose metabolism and EMT, the contribution of lipid metabolism is not still completely understood. Here, we studied epithelial and mesenchymal breast cancer cells by proteomic and lipidomic approaches and identified significant differences that characterised these models concerning specific metabolic enzymes and metabolites including fatty acids and phospholipids. Higher levels of monounsaturated fatty acids together with increased expression of enzymes of de novo fatty acid synthesis is the distinct signature of epithelial with respect to mesenchymal cells that, on the contrary, show reduced lipogenesis, higher polyunsaturated fatty acids level and increased expression of genes involved in the triglyceride (TAG) synthesis and lipid droplets formation. In the mesenchymal model, the diacylglycerol acyltransferase (DGAT)-1 appears to be the major enzyme involved in TAG synthesis and inhibition of DGAT1, but not DGAT2, drastically reduces the incorporation of labeled palmitate into TAG. Moreover, knockdown of β-catenin demonstrated that this metabolic phenotype in under the control of a network of transcriptional factors and that β-catenin has a specific role in the regulation of lipid metabolism in mesenchymal cells.

已有多项研究证实，存在与上皮间质转化（epithelial-mesenchymal transition, EMT）过程相关的特异性代谢程序。尽管学界对葡萄糖代谢与EMT之间的关联已有较为深入的认知，但脂质代谢在该过程中的贡献尚未完全阐明。本研究通过蛋白质组学与脂质组学方法，对上皮型及间质型乳腺癌细胞展开分析，鉴定出两类细胞模型在特定代谢酶与代谢物（包括脂肪酸与磷脂）层面的显著差异特征。相较于间质型乳腺癌细胞，上皮型细胞的标志性代谢特征为更高水平的单不饱和脂肪酸，以及脂肪酸从头合成相关酶的表达上调；反之，间质型细胞的脂肪生成能力减弱，多不饱和脂肪酸水平更高，且甘油三酯（TAG）合成与脂滴形成相关基因的表达出现上调。在间质型细胞模型中，二酰甘油酰基转移酶（DGAT）-1似乎是参与TAG合成的关键酶；抑制DGAT1（而非DGAT2）可显著降低标记棕榈酸向TAG的掺入效率。此外，通过β-连环蛋白（β-catenin）敲低实验证实，该代谢表型受一系列转录因子网络调控，且β-连环蛋白在间质型细胞的脂质代谢调控中发挥特异性作用。