Metabolic Reprogramming In Emt - Targeting Regulatory Nodes In Mesenchymal Cells

To combat cancer we have to avoid development of resistant and metastatic disease. Breast cancer cells can switch from an epithelial to mesenchymal phenotype through a process called epithelial to mesenchymal transition/EMT. Emerging evidence suggests that this process is vital to avoid treatment pressure and to gain metastatic capacity. Furthermore, recent literature shows that metabolic reprogramming is an essential attribute of cellular plasticity. Metabolic targeting could therefore be an attractive possibility to prevent development of resistance and metastatic dissemination. Here we tried to understand the metabolic phenotype of EMT and the mechanisms linking the metabolic programs to cellular plasticity. We also aimed to unravel compensatory metabolic pathways and use the metabolic inhibitors to sensitize breast cancer cells to conventional therapy. To that end we have investigated the metabolic signature of the D492 EMT cell model. The D492 cell line, established from human breast epithelial progenitor cells, has retained stem cell characteristics and has the ability to undergo EMT upon stromal (endothelial) influence, forming the mesenchymal D492M cells. Thus, D492 cell system has preserved the natural flexibility of breast epithelial progenitor cells, and constitutes a unique platform to unravel the factors responsible for stromal cell-induced cellular plasticity. We show that metabolic reprogramming is essential for induction of the mesenchymal phenotype using metabolomic profiling. Using Ultra performance liquid chromatography Mass Spectrometry and gene expression profiling we have created genome-scale metabolic models of D492 and D492M. Our data show that glycolytic flux and oxidative phosphorylation is higher in D492, however, D492M cells rely more on amino acid anaplerosis and fatty acid oxidation to fuel the TCA cycle. Glutamine and glucose tracing using NMR will give further insight into the difference in metabolism between the two cell lines. We have used these data to find metabolic targets that lock the cells in the epithelial state or identify the means to induce lethality in the mesenchymal cells. Using the metabolic rewiring of EMT in the D492 cell model we can understand the mechanisms responsible for treatment resistance, identify compensatory metabolic pathways during treatment and find metabolic inhibitors that will sensitize BC cells to conventional therapy. Citation Format: Bylgja Hilmarsdottir, Skarphedinn Halldorsson, Maria T. Grinde, Anna Barkovskaya, Solveig Pettersen, Thorarinn Gudjonsson, Siver A. Moestue, Ottar Rolfsson, Gunhild M. Maelandsmo. Metabolic reprogramming in EMT - targeting regulatory nodes in mesenchymal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4412. doi:10.1158/1538-7445.AM2017-4412