Obese adipose tissue-derived extracellular vesicles enriched with glycolytic cargo promote colorectal cancer tumorigenesis

Obesity increases the risk of colorectal cancer (CRC) development, accelerates disease progression and is associated with decreased disease-free survival. Obesity adversely affects the visceral adipose tissue (VAT) leading to increased secretion of extracellular vesicles (EVs). However, the crosstalk between VAT and CRC tumor cells still remains unclear. EVs are lipid-membraned particles that transfer cargo to and/or induce signaling in other cells. Here, we characterized human VAT-derived non-obese (N-OB) and obese (OB) EVs and investigated the functional interaction between CRC cells and VAT-derived EVs. EVs were isolated from VAT obtained from obese (BMI>30) and non-obese patients (BMI<30). Unbiased proteomics revealed that compared to N-OB EVs, OB EVs were enriched with glycolytic enzymes like triose phosphate isomerase (TPI1). This enrichment was associated with increased TPI1 protein levels in CRC cells and elevated glycolytic activity. OB EV-treated cells also exhibited increased stemness-associated genes, 3D-spheroid formation and Apc min/+ tumoroid self-renewal capacity. In vivo , mice with an adipocyte-specific knockout of EV cargo sorting protein, Tsg101 ( Tsg101 ΔAd ), have altered EV cargo composition with reduced glycolytic enzyme levels. Functionally, Tsg101 ΔAd -EVs were able to protect against high-fat diet (HFD)-induced increase in glycolysis and stem-like ability. Moreover, Apc min/+ : Tsg101 ΔAd mice were protected against HFD-induced enhanced tumorigenesis. Collectively, this study identifies adipocyte EVs, and its metabolic cargo, as an important regulator of CRC cell metabolism and function, promoting intestinal tumorigenesis.