Obesity is one of the main preventable causes of cancer, alongside smoking and alcohol consumption, and is linked to tumor aggressiveness. It is increasingly clear that signals produced by fat cells themselves are partly responsible for this phenomenon. Indeed, these cells can communicate with tumors, thereby promoting cancer aggressiveness. A research team from the Institute of Pharmacology and Structural Biology (IPBS, CNRS / Université Toulouse III - Paul Sabatier) has discovered the pivotal role played by small vesicles released by fat cells in melanoma (a skin cancer). These vesicles contain both the fuel and the machinery necessary for tumors to produce energy, explaining why obesity heightens skin cancer aggressiveness. This work was published online in The EMBO Journal on January 10th, 2020.
One means of communication between cells is the production of small entities called "extracellular vesicles" or EV. These EV carry a multitude of different molecules: proteins, lipids and even nucleic acids. Once released by cells, EV act as shuttles to transfer materials to other cells, which can thereby change their behavior. Three years ago, members of Catherine Muller's research team showed that the EV produced by fat cells are internalized by melanoma cells and make them more aggressive by boosting their metabolism. However, the precise mechanisms of this process remained unknown. Now, this same team has furthered the characterization of fat cell EV and identified the molecules within these EV that boost cancer cell metabolism.
Using an innovative technique, also developed at the IPBS in collaboration with Odile Schiltz's team, these scientists identified all of the proteins that are shuttled from fat cells to melanoma cells by EV. This is the first time that each and every protein transferred by EV from one cell type to another has been identified. Thereby, these researchers showed that fat cell EV provide tumor cells with the protein machinery necessary to process fatty acids to produce energy, and not only that! In fact, these EV also transport the fuel required for this process, fatty acids themselves. This simultaneous supply of machinery and fuel boosts fatty acid metabolism and energy production in melanoma cells, a process that in turn increases their aggressiveness. Furthermore, in obesity, fat cell EV contain more fatty acids, increasing metabolism even further, leading to heightened cancer cell aggressiveness.
In addition, these scientists have shown some of the excess transferred fatty acids are stored in the cancer cells within specialized compartments called lipid droplets. They can then be released over time to be used for energy production within mitochondria, structures that act as the powerhouses of cells. After treatment with fat cell EV, both lipid droplets and mitochondria are relocated to the extremities of cancer cells. This helps the cells to migrate and invade surrounding tissues with better efficiency by providing energy directly to the areas in which it is required.
This study demonstrates that fat cell EV act as "all-in-one" packages that deliver both the machinery and the fuel necessary to feed melanoma metabolism, furthering our understanding of the impact of fat cells on tumors, especially in obesity, and improving our knowledge of EV
Fat cells vesicles are "all-in-one" packages that stimulate tumor aggressiveness through metabolic remodeling Fat cells secrete vesicles containing the fuel (fatty acids) and the machinery (enzymes) necessary to produce energy. In cancer cells, these fatty acids are stored in lipid droplets and then used over time by mitochondria to produce energy (a process called fatty acid oxidation or FAO), which increases cell migration and, potentially, metastasis. In obesity, EV contain more fuel, potentiating their effect on tumor metabolism and aggressiveness
Emily Clement*, Ikrame Lazar*, Camille Attané, Lorry Carrié, Stéphanie Dauvillier, Manuelle Ducoux-Petit, David Esteve, Thomas Menneteau, Mohamed Moutahir, Sophie Le Gonidec, Stéphane Dalle, Philippe Valet, Odile Burlet-Schiltz, Catherine Muller and Laurence Nieto. Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells. The EMBO Journal. DOI of the article: 10.15252/embj.2019102525
Laurence Nieto | Laurence.Nieto@ipbs.fr | 05 61 17 55 09
Catherine Muller | Catherine.Muller@ipbs.fr | 05 61 17 59 32
Press: Francoise Viala | Communication@ipbs.fr | 06 01 26 52 59