Infoscience

Thesis

GLUT1 and GLUT3 in non-small cell lung cancer

While altered metabolism is a well-established tumor cell trait, the specifics of metabolic rewiring during cancer development and progression are yet to be fully understood. The Warburg effect, or aerobic glycolysis, has been described in a wide array of malignancies and has long been considered as an inefficient mean to fill energetic requirements. Emerging evidence however supports a role that extends beyond that, with glycolytic intermediates diverting to anabolic pathways to allow growth and proliferation. Importantly, the first and most critical rate-limiting step in glycolysis is glucose uptake. Fittingly, high affinity, high capacity glucose transporters such as GLUT1 and to a lesser extent GLUT3, are upregulated in cancer. Given the centrality of glycolysis in tumor biology and reported clinical observations relating to glucose transporter expression patterns, the present work focuses on characterizing the role of GLUT1 and GLUT3 in the context of non-small cell lung cancer (NSCLC), the most prevalent histological subtype of lung cancer. Linking glucose metabolism and a program involved in early steps of metastasis, part of the findings uncovers an aberrant expression of GLUT3 as integral to the epithelial-mesenchymal transition (EMT) in NSCLC. Indeed, a unique association between GLUT3 and a mesenchymal status is observed in a panel of human NSCLC cell lines. Furthermore, GLUT3 expression is increased during EMT by a mechanism that involves direct binding of EMT mediating transcription factor ZEB1 to the GLUT3 (SLC2A3) gene. Data also supports a functional role of GLUT3 in proliferation, as inhibiting GLUT3 expression reduces glucose import and proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. In an analysis of a large microarray data collection of human NSCLC samples, GLUT3 expression is found to correlate with EMT markers, and is prognostic of poor overall survival. Taken collectively, the data reveal an important role for GLUT3 in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Owing to the restricted expression of this transporter in healthy individuals, its presence in lung tumor cells may represent a noteworthy prospect for targeted therapy. The contrastingly ubiquitous nature of GLUT1 in normal and transformed tissue warrants in vivo investigation to determine expression patterns and contribution tumor development. To that end, generation of autochthonous lung cancer mouse models allows assessment of the effect of tumor exclusive GLUT1 loss. Ensuing preliminary results allude to a possible role of GLUT1 in specific histological lesions. The significance of this specificity is currently under investigation.

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