ORIGINAL RESEARCH article

Front. Oncol.

Sec. Cancer Metabolism

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1568524

This article is part of the Research TopicObesity, Diabetes, and Their Impact on CancerView all 6 articles

Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue

Provisionally accepted
Carol  Costa EncarnaçãoCarol Costa Encarnação1,2Carolinne  AmorimCarolinne Amorim3Victor  Aguiar FrancoVictor Aguiar Franco1,2Luiz Gabriel  Xavier BotelhoLuiz Gabriel Xavier Botelho1,2Ronan Christian  dos SantosRonan Christian dos Santos4Isadora  Ramos-AndradeIsadora Ramos-Andrade5Luiz Guilherme  Kraemer-AguiarLuiz Guilherme Kraemer-Aguiar6Christina  Barja-FidalgoChristina Barja-Fidalgo7João Alfredo  MoraesJoão Alfredo Moraes3Mariana  Renovato-MartinsMariana Renovato-Martins1,8*
  • 1Institute of Biology, Federal Fluminense University, Niterói, Brazil
  • 2Programa de Pós-Graduação em Biociências, UERJ, RIO DE JANEIRO, Brazil
  • 3Laboratório de Biologia Redox, CCS, UFRJ, RIO DE JANEIRO, Brazil
  • 4Instituto de Biofísica, UFRJ, RIO DE JANEIRO, Brazil
  • 5Department of Radiation Oncology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States
  • 6Obesity Unit, Multiuser Clinical Research Center, UERJ, RIO DE JANEIRO, Brazil
  • 7Laboratório de Farmacologia Celular e Molecular, IBRAG, UERJ, RIO DE JANEIRO, Brazil
  • 8Laboratório de Inflamação e Metabolismo, IB, UFF, Niterói, Brazil

The final, formatted version of the article will be published soon.

Leptin, 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). MDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals. Our 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). Overall, 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.

Keywords: Leptin, Obesity, Adipose Tissue, extracellular vesicles, breast cancer

Received: 30 Jan 2025; Accepted: 30 Apr 2025.

Copyright: © 2025 Encarnação, Amorim, Franco, Botelho, dos Santos, Ramos-Andrade, Kraemer-Aguiar, Barja-Fidalgo, Moraes and Renovato-Martins. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mariana Renovato-Martins, Institute of Biology, Federal Fluminense University, Niterói, Brazil

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