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Imaging Chemistry and Biology (pre-2019)

Imaging glycogenesis as a novel biomarker of drug-induced quiescence and senescence

Project ID: 2015_207

Student: Cen Chen

1st supervisor: Eric Aboagye, Imperial College London
2nd supervisor: Ralph Sinkus, King’s College London

Quiescence and by extension senescence are important cancer phenotypes that have not to date been described by molecular imaging. Of the targets known to be regulated by this phenotype, glycogen synthesis is perhaps the most optimal for non-invasive ‘tracing’. Glycogen is a multi-branched glucose polysaccharide that in humans is synthesised (glycogenesis) and stored primarily by liver and muscle cells, and physiologically functions as a secondary energy source. While the high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized, and exploited with 18F-2-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) to image tumours clinically, enhanced glycogenesis in cancer is less well understood. Distinct from our perception of the cancer cell as a cell deficient in energy stores requiring glucose uptake and glycolysis to meet energy demands, emerging data suggest that the quiescent state (high proportions of cancer cells normally exist in this state) can induce glycogen storage in cancer cells and buffer bio-energetic stress. To provide biologic insights into physiologic regulation of glycogen metabolism, we recently developed a non-invasive method to image glycogen storage via 18F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine positron emission tomography (18F-NFTG-PET) (Witney et al Cancer Res 2014).

Specificity of glycogen labelling was demonstrated by isolating 18F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1 (GYS1), which inhibited 18F-NFTG uptake, while oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We have presented preliminary data to show that the rate of glycogenesis is cell cycle-regulated, enhanced during the non-proliferative state of a cancer cell line. In this cell line, 18F-NFTG but not 18F-FDG uptake increased proportionally with cell density and G1/G0 arrest.

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