Adipocyte vesicles: ‘all-in-one’ packages that stimulate tumor mitochondrial metabolism and dynamics

Abstract

Extracellular vesicles are emerging key actors in adipocyte communication. Notably, small extracellular vesicles shed by adipocytes promote melanoma aggressiveness through fatty acid oxidation, with a heightened effect in obesity. However, the vesicular actors and cellular processes involved remain largely unknown. Here, we elucidate the mechanisms linking adipocyte extracellular vesicles to metabolic remodeling and cell migration. We show that adipocyte vesicles stimulate melanoma fatty acid oxidation by providing both enzymes and substrates. In obesity, the heightened effect of extracellular vesicles depends on increased transport of fatty acids, not fatty acid oxidationrelated enzymes. These fatty acids, stored within lipid droplets in cancer cells, drive fatty acid oxidation after release through lipophagy. This increase in mitochondrial activity redistributes mitochondria to membrane protrusions of migrating cells, which is necessary to increase cell migration in the presence of adipocyte vesicles. Our results provide key insights into the role of extracellular vesicles in the metabolic cooperation that takes place between adipocytes and tumors with particular relevance in obesity.

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

“…While the role of cancer cell-derived EVs in manipulating cells in the tumor microenvironment including adipocytes is well established [ 181 , 182 , 183 ], very little attention has been given to the bidirectional role EVs play in adipocyte-cancer cell communication, and particularly the influence of adipocyte-derived EVs on tumor cell behavior. Nevertheless, a small number of recent studies demonstrate a link between adipocyte EVs and tumor progression in obesity-driven lung cancer [ 184 ], breast cancer [ 185 , 186 ] and melanoma [ 180 , 187 ].…”

“…Thus differences in the cargo content of these EVs as opposed to the sheer number of vesicles are most likely responsible for this heightened effect. Recent in-depth labeling experiments indicate that around 30% of the proteins within the adipocyte EVs are sufficiently transferred to melanoma tumor cells, and these include proteins involved in EV transport, the transport and storage of FAs, mitochondrial FAO and oxidative phosphorylation [ 187 ]. Efforts to understand how an obese state heightens the effect of adipocyte EVs on FAO-induced functions of melanoma cells have revealed that the level of FAO enzymes in melanoma tumor cells is unaltered following uptake of obese versus lean derived EVs.…”

“…In contrast adipocyte EV supply of FAs and subsequent trafficking to melanoma cells was increased under obese conditions, resulting in enhanced substrate availability and FAO, and the altered mitochondrial dynamics that is critical to melanoma cell migration and invasion. Thus in the obese setting, it is the increased transfer of substrate (e.g., FA) and not machinery (FAO-related enzymes) that enhance FAO in recipient melanoma cancer cells [ 187 ].…”

Interaction between adipose tissue and cancer cells: role for cancer progression

“…In melanoma it has been demonstrated that extracellular vesicles carry proteins involved in fatty acid and glucose oxidation along with metabolic substrates inducing metabolic reprogramming in cancer cells [64,65]. These extracellular vesicles are involved in the promotion of cancer cell migration and invasion by adipocytes [64,65].…”

“…In melanoma it has been demonstrated that extracellular vesicles carry proteins involved in fatty acid and glucose oxidation along with metabolic substrates inducing metabolic reprogramming in cancer cells [64,65]. These extracellular vesicles are involved in the promotion of cancer cell migration and invasion by adipocytes [64,65]. Furthermore adipocytes grown in high-fat diet have a higher secretion of extracellular vesicles which induce a more pronounced effect on fatty acid oxidation in cancer cells due to enhanced lipid transfer but not through protein transfer [64,65].…”