Fatty acid profile in relative content (%). Qualitative analysis was calculated by dividing each raw area by the sum of total raw areas. Dash (‘-‘) represents lipid species that were not identified in the sample. Legend: CTR (control), ETO (etomoxir, 100 µM).
ARTICLE ABSTRACT
Most cancer related deaths are due to metastases. Systemic factors, such as lipid-enriched environments (as low-density lipoprotein (LDL)-cholesterol), favor breast cancer, including triple negative breast cancer (TNBC) metastasis formation. Mitochondria metabolism impacts TNBC invasive behavior but its involvement in a lipid-enriched setting is undisclosed. Here we show that LDL increases lipid droplets, induces CD36 and augments TNBC cells migration and invasion in vivo and in vitro. LDL induces higher mitochondrial mass and network spread in migrating cells, in an actin remodeling-dependent manner, and transcriptomic and energetic analyses revealed that LDL renders TNBC cells dependent on fatty acids (FAs) usage for mitochondrial respiration. Indeed, engagement on FA transport into the mitochondria is required for LDL-induced migration and mitochondrial remodeling. Mechanistically, LDL treatment leads to mitochondrial long chain fatty acid (LCFA) accumulation and increase reactive oxygen species (ROS) production. Importantly, CD36 or ROS blockade abolished LDL-induced cell migration and mitochondria metabolic adaptations. Our data suggest that LDL induces TNBC cells migration by reprogramming mitochondrial metabolism, revealing a new vulnerability in metastatic breast cancer.
