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Updated: Jan 5, 2026
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression
Esmeralda Ramirez-Peña1, James Arnold2, Vinita Shivakumar3
1National Cancer Institute, Cancer Prevention Fellowship Program, Division of Cancer Prevention, Bethesda, MD 20892, USA. esmeralda.ramirez-pena@nih.gov.
Abstract:
Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies.
Insights
Breast cancer cells undergoing epithelial to mesenchymal transition (EMT) lose glutamine dependence. Restoring GLS2 expression in mesenchymal cells inhibits EMT and may increase susceptibility to chemotherapy.
Area of Science:
- Molecular Biology
- Cancer Metabolism
- Cellular Differentiation
Background:
- Metastatic breast cancer poses a significant threat, driving the urgent need for novel therapeutic targets.
- Understanding the bioenergetic shifts during epithelial to mesenchymal transition (EMT) is crucial for developing anti-metastasis strategies.
Purpose of the Study:
- To investigate the bioenergetic changes associated with EMT in breast cancer cells.
- To identify key metabolic regulators involved in EMT and their potential as therapeutic targets.
Main Methods:
- Comparative analysis of metabolic activities and gene expression between epithelial and mesenchymal breast cancer cells.
- Manipulation of GLS2 expression and FOXC2 (a transcription factor) levels to assess their impact on cell metabolism and EMT.
- Correlation analysis of GLS2 expression with patient survival data.
Main Results:
- GLS2 (glutaminase) expression is inversely correlated with EMT; its down-regulation promotes glutamine independence and reduced mitochondrial activity.
- Restoring GLS2 expression in GLS2-negative cells reverses these effects, enhancing glutamine utilization and inhibiting stem-cell properties.
- Inhibition of FOXC2 restores GLS2 expression and glutamine utilization in mesenchymal cells.
- High GLS2 expression in breast cancer patients is linked to improved survival outcomes.
Conclusions:
- Epithelial breast cancer cells depend on glutamine, while EMT induces glutamine independence.
- Targeting GLS2 can induce a metabolic shift in mesenchymal cancer cells, potentially sensitizing them to chemotherapy.
- GLS2 and its regulation of EMT represent a promising avenue for treating metastatic breast cancer.
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