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bioRxiv · 10.1101/2024.02.18.580900

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells

Santiappillai, N.·Cao, Y.·Hakeem-Sanni, M. F.·Yang, J. Y. H.·Quek, L.-E.·Hoy, A. J.
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Abstract

Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of lactate and glutamine metabolism, and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.

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Santiappillai, N., Cao, Y., Hakeem-Sanni, M. F., Yang, J. Y. H., Quek, L.-E., Hoy, A. J.. 2024-02-21. Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells. https://doi.org/10.1101/2024.02.18.580900

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