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2020-04-21

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/186243

Identifying strategies to target the metabolic flexibility of tumours

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https://doi.org/10.1038/s42255-020-0195-8

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Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.

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Tumors, Àcids grassos, Metabolisme

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Tumors, Fatty acids, Metabolism

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Articles publicats en revistes (Ciències Fisiològiques)

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MÉNDEZ-LUCAS, Andrés, LIN, Wei, DRISCOLL, Paul c., LEGRAVE, Nathalie, NOVELLASDEMUNT, Laura, XIE, Chencheng, CHARLES, Mark, WILSON, Zena, JONES, Neil p., RAYPORT, Stephen, RODRÍGUEZ JUSTO, Manuel, LI, Vivian, MACRAE, James i., HAY, Nissim, CHEN, Xin, YUNEVA, Mariia. Identifying strategies to target the metabolic flexibility of tumours. _Nature Metabolism_. 2020. Vol. 2, núm. 4, pàgs. 335-350. [consulta: 20 de gener de 2026]. ISSN: 2522-5812. [Disponible a: https://hdl.handle.net/2445/186243]

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