Author, as appears in the article.: Cuyas, Elisabet; Fernandez-Arroyo, Salvador; Verdura, Sara; Lupu, Ruth; Joven, Jorge; Menendez, Javier A.;
Department: Medicina i Cirurgia
URV's Author/s: FERNANDEZ ARROYO, SALVADOR / Joven Maried, Jorge
Keywords: Therapy resistance Respiration Resistance Phenotypic screening Oxidation Mitochondria Metastasis Metabolism Inhibition Dehydrogenase Confers Complex iii Cancer stem-cells Breast cancer
Abstract: Simple Summary Epithelial-to-mesenchymal transition (EMT) is a cellular program that enables epithelial cells to transition toward a mesenchymal phenotype with augmented cellular motility. Although EMT is a fundamental, non-pathological process in embryonic development and tissue repair, it also confers biological aggressiveness to cancer cells, including invasive behavior, tumor- and metastasis-initiating cancer stem cell activity, and greater resistance to all the cancer treatment modalities. Whereas alterations in the metabolic microenvironment are known to induce EMT, it is also true that the EMT process involves a very marked metabolic remodeling. However, whether there is a causal or merely an ancillary relationship between metabolic rewiring and the EMT phenomenon has not yet been definitively clarified. Here, we combined several technology platforms to assess whether the accompanying changes in the metabolic profile and mitochondria functioning that take place during the EMT process are independent or not of the non-tumorigenic versus tumorigenic nature of epithelial cells suffering a mesenchymal conversion. Understanding the metabolic basis of the non-tumorigenic and tumorigenic EMT provides fundamental insights into the causation and progression of cancer and may, in the long run, lead to new therapeutic strategies. 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-Ras(V12)-driven tumorigenic backgrounds possess unique metabolic fingerprints. We profiled mitochondrial-cytosolic 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. "Upper" and "lower" 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, beta-oxidation substrates including palmitoyl-carnitine, 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.
Thematic Areas: Oncology Medicina iii Cancer research
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: jorge.joven@urv.cat
Author identifier: 0000-0003-2749-4541
Record's date: 2024-09-07
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.mdpi.com/2072-6694/14/24/6214
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Cancers. 14 (24):
APA: Cuyas, Elisabet; Fernandez-Arroyo, Salvador; Verdura, Sara; Lupu, Ruth; Joven, Jorge; Menendez, Javier A.; (2022). Metabolomic and Mitochondrial Fingerprinting of the Epithelial-to-Mesenchymal Transition (EMT) in Non-Tumorigenic and Tumorigenic Human Breast Cells. Cancers, 14(24), -. DOI: 10.3390/cancers14246214
Article's DOI: 10.3390/cancers14246214
Entity: Universitat Rovira i Virgili
Journal publication year: 2022
Publication Type: Journal Publications
Repositori URV