EMT-induced metabolite signature identifies poor clinical outcome

// Salil Kumar Bhowmik 1, 2, 3, * , Esmeralda Ramirez-Pena 4, * , James Michael Arnold 1, 2, 3, * , Vasanta Putluri 1, 2, 3 , Nathalie Sphyris 4 , George Michailidis 5 , Nagireddy Putluri 1, 2, 3 , Stefan Ambs 6 , Arun Sreekumar 1, 2, 3 , Sendurai A. Mani 4 1 Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA 2 Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, TX, USA 3 Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA 4 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Statistics, University of Michigan, Ann Arbor, MI, USA 6 Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA * These authors have contributed equally to this work Correspondence to: Sendurai A. Mani, e-mail: smani@mdanderson.org Arun Sreekumar, e-mail: arun.sreekumar@bcm.edu Keywords: EMT, breast cancer, metabolism, metabolic reprogramming, LC-MS metabolomics Received: April 21, 2015      Accepted: July 20, 2015      Published: August 01, 2015 ABSTRACT Metabolic reprogramming is a hallmark of cancer. Epithelial-mesenchymal transition (EMT) induces cancer stem cell (CSC) characteristics and promotes tumor invasiveness; however relatively little is known about the metabolic reprogramming in EMT. Here we show that breast epithelial cells undergo metabolic reprogramming following EMT. Relative to control, cell lines expressing EMT transcription factors show ≥1.5-fold accumulation of glutamine, glutamate, beta-alanine and glycylleucine as well as ≥1.5-fold reduction of phosphoenolpyruvate, urate, and deoxycarnitine. Moreover, these metabolic alterations were found to be predictive of overall survival (hazard ratio = 2.3 (95% confidence interval: 1.31–4.2), logrank p -value = 0.03) and define breast cancer molecular subtypes. EMT-associated metabolites are primarily composed of anapleurotic precursors, suggesting that cells undergoing EMT have a shift in energy production. In summary, we describe a unique panel of metabolites associated with EMT and demonstrate that these metabolites have the potential for predicting clinical and biological characteristics associated with patient survival.