Hold the Sugar

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Science Translational Medicine  08 Jan 2014:
Vol. 6, Issue 218, pp. 218ec7
DOI: 10.1126/scitranslmed.3008245

Renewed interest in the Warburg effect—that tumor cells rely predominantly on glycolysis for energy—has led to the inclusion of aberrant metabolic signaling as a “hallmark” of cancer. This inclusion was prompted by studies showing that altered cellular metabolism is symptomatic of oncogenic signaling. However, proving the converse—that altered metabolism is not just a consequence but also a cause of oncogenic signaling—has proven difficult because most studies rely on tissue culture plastic, in which such pathways are artificially heightened and there is only one relevant readout: growth. In this context, one cannot study the true hallmark of cancer: loss of tissue architecture.

It is in this light that the recent findings of Onodera et al. can be appreciated. Using a three-dimensional (3D) model of breast tumor progression, where nonmalignant and malignant breast epithelial cells assume morphologies much like they would in vivo, the authors altered glucose uptake and observed how it affected cellular phenotype. Inhibition of glucose metabolism, glucose transport, or reduction of glucose in culture medium suppressed oncogenic signaling pathways and reverted the phenotype of malignant breast epithelial cells so that they growth-arrested and assumed proper basal polarity, a marker of normal (healthy) tissue architecture. Conversely, enhancing glucose uptake in nonmalignant breast epithelial cells by up-regulating glucose transporter expression resulted in increased oncogenic signaling, enhanced growth, and loss of tissue polarity. Inhibition of known mediators of glucose metabolism [5′ adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and hypoxia-inducible factors (HIFs)] only served to suppress growth in 3D but did not affect tissue architecture; malignant cells retained aberrant morphology. This implied that noncanonical molecules integrate glucose signaling and tissue architecture in 3D. Onodera and coauthors subsequently pinpointed Rap1 and O-linked N-acetylglucosamine (O-GlcNAc) pathways as the critical metabolic mediators.

This work provides compelling evidence for prevention and intervention strategies aimed at reducing dietary glucose consumption. By targeting integrators of glucose metabolism and oncogenic signaling pathways, it may be possible to preserve tissue architecture despite aberrant metabolic cues and thus prevent cancer occurrence. On a more basic level, their work argues for 3D models to study pathways that link extracellular and intracellular signaling in cancer and other disease states in context.

Y. Onodera et al., Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J. Clin. Invest. 124, 367–384 (2014). [Full Article]

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