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bioRxiv · 10.64898/2026.02.08.704727

Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles

Bustamante Marin, X. M.·Grindstaff, E.·Rayyan, L. A.·Alwarawrah, Y.·Rezeli, E.·MacIver, N. J.·Teegarden, D.·Hursting, S. D.
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Abstract

Obesity alters systemic metabolism and immune function, yet how obesity and tumor progression regulate extracellular vesicle (EV) composition and function within the tumor microenvironment remains unclear. Using a preclinical model of diet-induced obesity (DIO) and triple-negative breast cancer (TNBC), we investigated how obesity and tumor stage shape the proteomic composition of EVs from visceral adipose tissue (VAT-EVs) and mammary tumors (tumor-EVs), and how these EVs regulate immune and tumor cell metabolism. Orthotopically transplanted metM-Wntlung tumors were classified as early ([~]0.5 cm3) or late ([~]1.0 cm3), and EV proteomes were analyzed by mass spectrometry. At early stages, tumor-EVs from DIO mice, compared with control lean mice, were depleted in immune-related proteins, whereas VAT-EVs were enriched in mitochondrial and fatty acid oxidation proteins. In contrast, at later stages, tumor-EVs from DIO mice were enriched in lipid metabolism and oxidative stress-associated proteins, while VAT-EVs exhibited loss of mitochondrial proteins consistent with metabolic dysfunction. Functionally, tumor-EVs and VAT-EVs differentially regulated CD8 T cell mitochondrial activity and cytokine production and induced distinct, stage-dependent metabolic reprogramming in non-aggressive epithelial-like (E-Wnt) versus mesenchymal-like (M-Wnt) tumor cells. These findings suggest that obesity and tumor progression dynamically reshapes EV cargo, enabling EV-mediated metabolic reprogramming that may contribute to immune suppression and TNBC progression.

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Bustamante Marin, X. M., Grindstaff, E., Rayyan, L. A., Alwarawrah, Y., Rezeli, E., MacIver, N. J., Teegarden, D., Hursting, S. D.. 2026-02-10. Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles. https://doi.org/10.64898/2026.02.08.704727

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