Hypertrophic adipocytes increase extracellular vesicle-mediated lipid release and reprogram breast cancer cell metabolism

Obesity worsens cancer-specific survival and all-cause mortality for women diagnosed with breast cancer. Rich in adipose tissue, the breast exhibits increased adipocyte size in obesity, which correlates with poor prognosis. However, adipocyte size is highly heterogeneous as adipose tissue expands through both hyperplasia and hypertrophy; and adipocyte size can increase independently of weight gain. Despite these observations, the impact of adipocyte size on breast cancer cell behavior remains unclear due to insufficient approaches to isolate adipocytes based on size and maintain them in culture for mechanistic studies. Here, we develop strategies to culture size-sorted adipocytes from two mouse models of obesity and test their functional impact on tumor cell malignancy. We find that large adipocytes are transcriptionally distinct from small adipocytes and are enriched for gene sets related to adipose tissue dysfunction, including altered lipid processing. In coculture studies, large adipocytes promote lipid accumulation in breast cancer cells, and enhance their migration, proliferation, and aerobic metabolism in a manner dependent on fatty acid oxidation. These changes coincide with increased release of extracellular vesicles by large versus small adipocytes, which transfer lipid to recipient tumor cells. Moving forward, our findings suggest that adipocyte size could serve as a prognostic biomarker for women with breast cancer and help identify new therapeutic targets to advance clinical outcomes for these patients.