Obesity-associated plasma exosomes drive epithelial-to-mesenchymal transition and metastasis in mouse triple negative breast cancer models
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Abstract
Breast cancer, the most diagnosed cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes isolated from obese mice raised on a high-fat diet (HFD) induce epithelial-mesenchymal transition features in TNBC cells, leading to increased migration in vitro and enhanced metastasis in vivo. We build on our previous reports which demonstrated that plasma exosomes isolated from type 2 diabetic patients and exosomes secreted by insulin-resistant mouse adipocytes, upregulate key transcriptional signatures of epithelial-mesenchymal transition in breast cancer cells. In the present study, pathway enrichment analysis of our quantitative phosphoproteomics data demonstrated that TNBC cells exposed to plasma-derived exosomes from mice on a HFD exhibit broad activation of Rho-GTPase signaling (most notably Rac1 and RhoA), which drive actin-cytoskeleton remodeling and increased cell motility, a recognized hallmark of cancer invasion and metastasis. These findings identify Rho-GTPases pathways as promising therapeutic targets and exosomes as circulating biomarkers to stratify TNBC patients with metabolic comorbidities.
Description
2025