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Elisabeth Smolle
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P62 - Tumor Biology and Systems Biology - Basic and Translational Science - Metabolomics (ID 200)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P62.08 - Expression Pattern and Prognostic Significance of Gluconeogenesis Enzymes in Lung Cancer. (ID 3321)
00:00 - 00:00 | Presenting Author(s): Elisabeth Smolle
- Abstract
Introduction
Inhibition of glycolysis may become a future therapeutic approach in aggressive cancers, including lung cancer. Gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was only recently discovered to partially circumvent the pathway of glycolysis in lung cancer cells, especially under low-glucose conditions. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood.
Methods
We analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution of these enzymes was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was evaluated, based on The Cancer Genome Atlas (TCGA) datasets.
Results
PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. Yet, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells, was frequent. PCK2 expression was associated with significantly improved overall survival in the adenocarcinoma subtype, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin, and considering hypoxia as a mediator of both, glycolysis and gluconeogenesis, in NSCLC cells in vitro. PCK1/2 expression was enhanced in metastases compared to primary tumors, probably due to differences in the tumor microenvironment.
Conclusion
The results of this study show both glycolysis and gluconeogenesis being activated in NSCLC in a tumor size- and oxygenation-modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered when targeting cancer cell metabolism in future therapeutic approaches.
