Carcinomas have two broadly distinct modes of invasion: collective and individual. Collective invasion is characterized as groups of cells that migrate while retaining cell-cell contacts. Individual invasion occurs through mechanisms such as the acquiring of mesenchymal-like features by cancer cells. While these different modes of invasion have been well studied at the genomic and transcriptional levels, their metabolic alterations remain much less understood. To address this deficiency, we performed untargeted NMR metabolomics, in conjunction with RNA-seq, on two variants of MCF7, a widely used breast cancer cell line. We report herein several findings. First, the two MCF7 variants, one parental (referred to as MCF-7 hereafter) and another having undergone many passages (referred to as Augusta hereafter), differ morphologically, with MCF-7 being more epithelial and Augusta being more mesenchymal-like. Importantly, fibroblast co-culture experiments indicate that MCF-7 cells resemble collective invasion, while Augusta cells resemble individual invasion. Furthermore, both scratch-assay and gene set enrichment analysis of RNA-seq data indicate that Augusta cells are more invasive. Second, our NMR metabolomics analysis reveals that branched chain amino acids (BCAAs) represent a significant metabolic difference between MCF-7 and Augusta cells. Partial least squares discriminant analysis of the metabolomics data identified BCAAs as essential distinguishing features between the two cell lines. Specifically, compared to MCF-7 cells, BCAAs are significantly depleted inside Augusta cells, consistent with the upregulation of several key BCAA degradation genes. We hypothesize that Augusta cells can more efficiently utilize BCAAs, and are performing 13C-labeled BCAA flux analysis to test this hypothesis. Previous studies have shown that an aberrantly expressed BCAA metabolism gene sustains growth and enhances invasiveness of breast cancer cells. However, increased catabolism of BCAAs has not been reported in literature on this subject. Our simple cell line model allows for a deeper molecular understanding of BCAA metabolism in breast cancer cell invasion.

Citation Format: Maxwell B. Colonna, Arthur S. Edison, Shaying Zhao. A potential role of branched chain amino acid metabolism in breast cancer cell invasiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5270.