Marín de Mas, Igor BartoloméAguilar Fadó, EstherZodda, ErikaBalcells Nadal, CristinaMarín Martínez, SilviaDallmann, GuidoThomson, Timothy M.Papp, BalázsCascante i Serratosa, Marta2018-04-262018-04-262018-01-021553-734Xhttps://hdl.handle.net/2445/121900Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal-transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria.20 p.application/pdfengcc-by (c) Marin-de Mas, Igor et al., 2018http://creativecommons.org/licenses/by/3.0/esCèl·lules cancerosesCàncer de pròstataMetabolismeEpiteliCancer cellsProstate cancerMetabolismEpitheliuminfo:eu-repo/semantics/article6790732018-04-26info:eu-repo/semantics/openAccess29293497