EMT-induced metabolite signature identifies poor clinical outcome

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.

Divergent in vitro/in vivo responses to drug treatments of highly aggressive NIH-Ras cancer cells: a PET imaging and metabolomics-mass-spectrometry study

“…These results confirmed the key role of glucose (Figure 6, red arrows) and suggest the activation of the urea cycle pathway (Figure 6, yellow arrows) involved in ammonia removal and β-alanine involved in metabolic rewiring, like it occurs following epithelial-mesenchymal transition (EMT) [39, 46]. On the other hand, the significant increase in glycine levels found under a combined drugs treatment suggests that NIH-Ras tumors could activate multiple alternative pathways, such as the serine-glycine pathway [36], able to sustain the aggressive cell proliferation of NIH-Ras tumors in metabolic stress conditions (Figure 6, lilac arrows) [47, 48].…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…79). Another group identified a specific metabolic signature associated with the EMT process in breast cancer cells, which was associated with poor overall survival in breast cancer patients (80). In contrast, invasive breast cancer cells exhibit a shift toward OXPHOS metabolism, via a pathway dependent on the transcriptional coactivator, PGC-1a (peroxisome proliferator-activated receptor gamma coactivator-1a), which is a key regulator of mitochondrial biogenesis and metabolism.…”

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

“…Thus, glutamine can undergo glutaminolysis by glutamine synthetase to yield glutamate, which can be further deaminated into a-ketoglutarate and enter the TCA cycle. Glutamine and glutamate metabolism correlates with the expression of EMT-associated transcription factors (37) and glutaminolysis may serve as a driver of invasiveness of breast cancer cells (38). To analyze the contribution of glutamine to the aggressive behavior of 537S-ER-expressing cells, MCF-7 cells expressing either 537S-ER or WT-ER, were grown in the presence of E2 under glucose deprivation conditions (described under "Material and Methods").…”