Obesity-Linked Exosomes May Drive Tumor Aggressiveness in Triple-Negative Breast Cancer

Metabolic disorders, such as type 2 diabetes (T2D) and obesity, can drive tumor aggressiveness in triple-negative breast cancer (TNBC), according to study data published in BMC Cancer. The findings build on emerging research investigating the role of exosomes in cancer aggressiveness.¹

Breast cancer cell | Image Credit: © Mopic - stock.adobe.com

"Obesity and [T2D] are very common and already known to worsen many cancers,” Pablo Llevenes, lead author and PhD candidate in biomolecular pharmacology at Boston University Chobanian & Avedisian School of Medicine, said in coverage by Medical Xpress. “Our research shows one clear biological way, via exosomes, how being obese can make a deadly breast cancer subtype even more aggressive.”²

About 15% of all diagnoses of BC in the United States are TNBC, an aggressive subtype with few treatment choices since tumor cells lack human epidermal growth factor receptor 2, progesterone, and estrogen receptors. The absence of these common targets makes TNBC particularly difficult to treat, leaving patients with treatment options limited to cytotoxic agents like chemotherapy. The 5-year relative survival rate for TNBC is approximately 91%; however, this rate drops dramatically to about 12% for distant metastases.^1-3

There is growing interest in how TNBC is affected by metabolic disorders like T2D and obesity, which are both linked to more aggressive cancers and worse outcomes. Obesity is a chronic inflammatory condition that impairs how tissues respond to insulin. This ongoing inflammation leads to metabolic changes and the release of pro-inflammatory molecules—such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and leptin—into the bloodstream. These circulating factors can interact with tumors and their surrounding environment, helping to drive cancer growth and progression.¹

“However, the key causal elements that connect obesity-driven, systemic insulin resistance to increased metastatic burden and tumor progression remain poorly understood,” the authors wrote.¹

Researchers hypothesized that exosomes—small vesicles present in plasma or released by adipose tissue—may play a role in promoting tumor growth and aggressiveness, particularly in the context of obesity-driven metabolic dysfunction. To investigate this, they used a high-fat diet (HFD)–fed C57BL/6J mouse model to examine how obesity-related insulin resistance affects exosome production and function. Their focus was on how these exosomes influence the behavior of E0771 breast cancer cells, a commonly used model for TNBC, especially in the context of metabolic disease.¹

The study found that exosomes derived from HFD-induced obese, insulin-resistant mice had significantly different molecular content compared with those from lean, insulin-sensitive controls. When taken up by BC cells, these altered exosomes triggered notable molecular and phenotypic changes, including the promotion of a mesenchymal-like state—a hallmark of increased cancer aggressiveness.¹

The model's validity was confirmed through standard metabolic testing, including oral glucose tolerance tests and intraperitoneal insulin tolerance tests, which demonstrated impaired glucose clearance and insulin response. Additionally, the HFD group showed significant weight gain, consistent with obesity and systemic insulin resistance.¹

“The differential effects observed between exosomes derived from visceral adipose tissue and plasma suggest that circulating exosomes may have a more pronounced impact on promoting a mesenchymal and metastatic phenotype in TNBC cells,” the authors concluded. “Future research should explore therapeutic strategies targeting specific signaling pathways, such as Rac1, to mitigate the pro-metastatic effects of obesity-driven insulin resistance.”¹

REFERENCES

1. Llévenes P, Chen A, Lawton M, et al. Plasma exosomes in insulin resistant obesity exacerbate progression of triple negative breast cancer. BMC Cancer. July 9, 2025. Doi:10.1186/s12885-025-14447-8

2. Aggressive breast cancer triggered by obesity-related blood signals, study shows. Medical Xpress. July 9, 2025. Accessed July 9, 2025. https://medicalxpress.com/news/2025-07-aggressive-breast-cancer-triggered-obesity.html

3. Gerlach A. Sacituzumab govitecan-hziy plus pembrolizumab improves PFS in patients with metastatic triple-negative breast cancer. Pharmacy Times. April 24, 2025. https://www.pharmacytimes.com/view/sacituzumab-govitecan-hziy-plus-pembrolizumab-improves-pfs-in-patients-with-metastatic-triple-negative-breast-cancer