REPOSITORY > RESULTS

Abstract

Lipid droplets have recently been recognized as dynamic organelles found in most cells from prokaryotes to mammals. They are major regulators of lipid metabolism, trafficking and signaling, but their synthesis is also induced in cells exposed to various conditions of stress. Lipid droplets accumulate in cancer cells and are emerging as important factors for the plasticity of cancer metabolism and resilience to stress. However, mechanisms that drive lipid droplet turnover in cancer cells are far from being understood. The major objective of this dissertation was to define the principal ways in which lipid droplets are associated with cell survival and the function of aggressive triple-negative breast cancer (TNBC) cells during metabolic stress. By examining the roles of the major enzymes involved in lipid droplet turnover, diacylglycerol acyltransferase (DGAT) and adipose triglyceride lipase (ATGL), we have identified the contribution of lipid droplets to the resistance of TNBC cells against (1) nutrient and (2) lipotoxic stress and their ability to (3) drive the production of inflammatory lipid mediators. We show here that ATGL is involved in lipid droplet breakdown during starvation, but surprisingly, it is not essential for TNBC cell survival during starvation-induced nutrient stress. On the contrary, we found that ATGL-mediated lipolysis is an essential source of polyunsaturated fatty acids (PUFAs), which are used as precursors for the synthesis of eicosanoids and specialized pro-resolving mediators in starved TNBC cells, suggesting a novel role for lipid droplets in inflammatory signalling in cancer. Furthermore, our results reveal that the breakdown of lipid droplets induced by high concentrations of PUFAs is associated with oxidative stress-dependent cell death in TNBC cells, while low concentrations of PUFAs have the opposite effect – they increase the resistance of TNBC cells to starvation-induced stress. In line with a protective role of lipid droplets against the surge of exogenous PUFAs, we found that DGAT-mediated lipid droplet biogenesis reduces PUFA lipotoxicity. Most importantly, we have discovered two novel mechanisms through which lipid droplets protect cells from PUFA lipotoxicity. The first is the stimulation of lipid droplet biogenesis by the activity of secreted phospholipase A2, which hydrolyses membrane phospholipids and induces the incorporation of monounsaturated acyl chains in TAGs to effectively sequester PUFAs within lipid droplets. The second is the ability of ATGL to modulate PUFA-induced cell damage by regulating the release of PUFAs from lipid droplets. Our results reveal that lipid droplets integrate metabolic and signalling pathways that are associated with cancer cell stress resistance and are thus potential targets in the fight against aggressive breast cancer.