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Hungry for glutamine - Understanding the metabolism of breast cancer

Unlike other breast cancer types, triple negative breast cancer (TNBC) does not express the three most common biomarkers: The estrogen-, progesterone- and human epithelial growth factor (HER2) receptors. Therefore, patients with TNBC can neither benefit from hormonal therapies nor medicines that target the Her2 protein. Hence, there is a firm interest to develop new strategies particularly against TNBC. Scientists from e:Med alliance Her2Low led by Stefan Wiemann of the DKFZ studied the metabolic needs of this aggressive breast cancer subtype. Their study revealed that TNBC cells operate with altered metabolic and nutrient sensing pathways to sustain tumorigenesis and these alterations could potentially be targeted as a therapy approach.


What changes in the energy metabolism of breast cancer cells? To find the answer, the researchers focused on the GPT2, an enzyme that hangs between glycolysis and glutaminolysis, two pathways that cancer cells prefer over conventional energy pathway (citric acid cycle, or TCA cycle).


First, the scientists observed that GPT2 expression is higher in TNBC cells and that inhibiting the GPT2 enzyme restricts tumor growth. Evaluating changes in intracellular metabolites upon inhibition of the enzyme showed reduced alanine amounts as well as glutamine uptake into the cells. GPT2 blockage rewired the glucose metabolism. Prevention of glutaminolysis led to increased use of pyruvate (derived from glucose) and TCA cycle intermediates. Further, labelling carbon atoms of glucose revealed that the intermediates of TCA cycle are built mostly through incorporation of atoms from glucose and not glutamine. The researchers also observed increased activity of pyruvate carboxylase (PC), an enzyme that prepares pyruvate to enter into TCA cycle. Knockdown of both GPT2 and PC caused a significant decrease in tumor  cell numbers. Thus, the researchers concluded that combined targeting of these two enzymes could rise to a new therapy strategy.


What effects do the altered signalling pathways have owing to the changed glutamin consumption? In the next step, the scientists investigated this question. Global gene expression analysis revealed nutrient sensing pathway mTORC1 to be affected substantially. Knock-out (KO) of GPT2 compromised mTORC1 activity. In addition, it induced autophagy: self-eating, a process where the cells consume molecules in order to release more building blocks. Scientists concluded low intracellular amino acid levels caused by blocked alanine generation and lower glutamine uptake that reduced mTORC1 activity and triggered autophagy.
But how does the lack of GPT2 affect the organism? The scientists tested tumor growth in mice by injecting GPT2 KO cells. The tumors grew much slower and weighed less than in mice with normal TNBC cells. After seeing consistent results in vivo, they assessed a potential correlation between autophagy and GPT2 expression in patients. In a cohort of breast cancer patients, they observed that high GPT2 expression indeed correlates with autophagy marker p62 expression. These findings strengthened the connection between mTORC1 activity and glutaminolysis in breast cancer.

Cancer cells find alternative routes to their energy demands to continue tumorigenesis. Rather than conventional energy pathway, they utilize glycolysis and glutaminolysis to convert glucose into lactate and glutamine into α-ketoglutarate (α-Kg), respectively. Scientists focused on the enzyme GPT2, which converts glutamine to α-Kg to investigate the metabolic alterations of breast cancer cells. 

This is the first study to report a quantitative analysis of GPT2 in breast cancer patients and to uncover the relation between GPT2 activity, mTORC1 and autophagy in vitro, in vivo and in patients. Thus, it advances the current understanding of breast cancer metabolism. Findings in this study may help to develop therapy strategies against breast cancer.
 

Original publication:

Mitra, D., S. Vega-Rubin-de-Celis, N. Royla, S. Bernhardt, H. Wilhelm, N. Tarade, G. Poschet, M. Buettner, I. Binenbaum, S. Borgoni, M. Vetter, E. J. Kantelhardt, C. Thomssen, A. Chatziioannou, R. Hell, S. Kempa, K. Müller-Decker, and S. Wiemann (2020). "Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy." Int J Cancer. doi.org/10.1002/ijc.33456.

 

Alliance and contact person:

Her2low

Prof. Stefan Wiemann, DKFZ, Heidelberg, s.wiemann@dkfz.de

https://www.dkfz.de/en/mga