{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:10:17Z","timestamp":1778695817980,"version":"3.51.4"},"reference-count":108,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T00:00:00Z","timestamp":1671148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["PID2019-10455GB-I00"],"award-info":[{"award-number":["PID2019-10455GB-I00"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["PI22\/00297"],"award-info":[{"award-number":["PI22\/00297"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Epithelial-to-mesenchymal transition (EMT) is key to tumor aggressiveness, therapy resistance, and immune escape in breast cancer. Because metabolic traits might be involved along the EMT continuum, we investigated whether human breast epithelial cells engineered to stably acquire a mesenchymal phenotype in non-tumorigenic and H-RasV12-driven tumorigenic backgrounds possess unique metabolic fingerprints. We profiled mitochondrial\u2013cytosolic bioenergetic and one-carbon (1C) metabolites by metabolomic analysis, and then questioned the utilization of different mitochondrial substrates by EMT mitochondria and their sensitivity to mitochondria-centered inhibitors. \u201cUpper\u201d and \u201clower\u201d glycolysis were the preferred glucose fluxes activated by EMT in non-tumorigenic and tumorigenic backgrounds, respectively. EMT in non-tumorigenic and tumorigenic backgrounds could be distinguished by the differential contribution of the homocysteine-methionine 1C cycle to the transsulfuration pathway. Both non-tumorigenic and tumorigenic EMT-activated cells showed elevated mitochondrial utilization of glycolysis end-products such as lactic acid, \u03b2-oxidation substrates including palmitoyl\u2013carnitine, and tricarboxylic acid pathway substrates such as succinic acid. Notably, mitochondria in tumorigenic EMT cells distinctively exhibited a significant alteration in the electron flow intensity from succinate to mitochondrial complex III as they were highly refractory to the inhibitory effects of antimycin A and myxothiazol. Our results show that the bioenergetic\/1C metabolic signature, the utilization rates of preferred mitochondrial substrates, and sensitivity to mitochondrial drugs significantly differs upon execution of EMT in non-tumorigenic and tumorigenic backgrounds, which could help to resolve the relationship between EMT, malignancy, and therapeutic resistance in breast cancer.<\/jats:p>","DOI":"10.3390\/cancers14246214","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T08:41:41Z","timestamp":1671439301000},"page":"6214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolomic and Mitochondrial Fingerprinting of the Epithelial-to-Mesenchymal Transition (EMT) in Non-Tumorigenic and Tumorigenic Human Breast Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5353-440X","authenticated-orcid":false,"given":"Elisabet","family":"Cuy\u00e0s","sequence":"first","affiliation":[{"name":"Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17005 Girona, Spain"},{"name":"Girona Biomedical Research Institute, 17190 Girona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0147-1712","authenticated-orcid":false,"given":"Salvador","family":"Fern\u00e1ndez-Arroyo","sequence":"additional","affiliation":[{"name":"Eurecat, Centre Tecnol\u00f2gic de Catalunya, Centre for Omic Sciences, Joint Unit Eurecat-Universitat Rovira I Virgili, Unique Scientific and Technical Infrastructure (ICTS), 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-0423","authenticated-orcid":false,"given":"Sara","family":"Verdura","sequence":"additional","affiliation":[{"name":"Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17005 Girona, Spain"},{"name":"Girona Biomedical Research Institute, 17190 Girona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Lupu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology Laboratory, Mayo Clinic Minnesota, Rochester, MN 55905, USA"},{"name":"Mayo Clinic Cancer Center, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2749-4541","authenticated-orcid":false,"given":"Jorge","family":"Joven","sequence":"additional","affiliation":[{"name":"Unitat de Recerca Biom\u00e8dica (URB-CRB), Hospital Universitari de Sant Joan, Institut d\u2019Investigaci\u00f3 Sanitaria Pere Virgili, Universitat Rovira I Virgili, 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-4561","authenticated-orcid":false,"given":"Javier A.","family":"Menendez","sequence":"additional","affiliation":[{"name":"Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17005 Girona, Spain"},{"name":"Girona Biomedical Research Institute, 17190 Girona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nrc822","article-title":"Epithelial-mesenchymal transitions in tumour progression","volume":"2","author":"Thiery","year":"2002","journal-title":"Nat. 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