Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue
IntroductionLeptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose ti...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1568524/full |
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| author | Carol Costa Encarnação Carolinne Souza Amorim Victor Aguiar Franco Luiz Gabriel Xavier Botelho Ronan Christian Machado dos Santos Isadora Ramos-Andrade Luiz Guilherme Kraemer-Aguiar Christina Barja-Fidalgo João Alfredo Moraes Mariana Renovato-Martins |
| author_facet | Carol Costa Encarnação Carolinne Souza Amorim Victor Aguiar Franco Luiz Gabriel Xavier Botelho Ronan Christian Machado dos Santos Isadora Ramos-Andrade Luiz Guilherme Kraemer-Aguiar Christina Barja-Fidalgo João Alfredo Moraes Mariana Renovato-Martins |
| author_sort | Carol Costa Encarnação |
| collection | DOAJ |
| description | IntroductionLeptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).MethodMDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.ResultsOur findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin’s pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).DiscussionOverall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer. |
| format | Article |
| id | doaj-art-faac6ff751084f8a852bcee99a709657 |
| institution | OA Journals |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj-art-faac6ff751084f8a852bcee99a7096572025-08-20T02:26:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-05-011510.3389/fonc.2025.15685241568524Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissueCarol Costa Encarnação0Carolinne Souza Amorim1Victor Aguiar Franco2Luiz Gabriel Xavier Botelho3Ronan Christian Machado dos Santos4Isadora Ramos-Andrade5Luiz Guilherme Kraemer-Aguiar6Christina Barja-Fidalgo7João Alfredo Moraes8Mariana Renovato-Martins9Laboratory of Inflammation and Metabolism, Department of Cellular and Molecular Biology, Universidade Federal Fluminense, Rio de Janeiro, BrazilRedox Biology Laboratory, Programa de Farmacologia e Inflamação, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Inflammation and Metabolism, Department of Cellular and Molecular Biology, Universidade Federal Fluminense, Rio de Janeiro, BrazilLaboratory of Inflammation and Metabolism, Department of Cellular and Molecular Biology, Universidade Federal Fluminense, Rio de Janeiro, BrazilInstitute of Biophysics, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilDepartment of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, United StatesObesity Unit, Multiuser Clinical Research Center (CePEM), Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Cellular and Molecular Pharmacology, Institute of Biology Roberto Alcantara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilRedox Biology Laboratory, Programa de Farmacologia e Inflamação, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Inflammation and Metabolism, Department of Cellular and Molecular Biology, Universidade Federal Fluminense, Rio de Janeiro, BrazilIntroductionLeptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).MethodMDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.ResultsOur findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin’s pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).DiscussionOverall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer.https://www.frontiersin.org/articles/10.3389/fonc.2025.1568524/fullleptinobesityadipose tissueextracellular vesiclesbreast cancer |
| spellingShingle | Carol Costa Encarnação Carolinne Souza Amorim Victor Aguiar Franco Luiz Gabriel Xavier Botelho Ronan Christian Machado dos Santos Isadora Ramos-Andrade Luiz Guilherme Kraemer-Aguiar Christina Barja-Fidalgo João Alfredo Moraes Mariana Renovato-Martins Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue Frontiers in Oncology leptin obesity adipose tissue extracellular vesicles breast cancer |
| title | Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue |
| title_full | Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue |
| title_fullStr | Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue |
| title_full_unstemmed | Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue |
| title_short | Targeting the leptin receptor promotes MDA-MB-231 cells’ metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue |
| title_sort | targeting the leptin receptor promotes mda mb 231 cells metabolic reprogramming and malignancy the role of extracellular vesicles derived from obese adipose tissue |
| topic | leptin obesity adipose tissue extracellular vesicles breast cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1568524/full |
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