Mitochondrial metabolism drives hypercholesterolemia-induced breast cancer cell migration

Abstract Most cancer related deaths are due to metastases. Systemic factors, such as lipid-enriched environments (particularly 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-cholesterol induces CD36, increases lipid droplets and augments TNBC cells migration and invasion in vivo and in vitro. LDL increases mitochondrial mass and mitochondria spread in migrating cells, and energetic analyses revealed that LDL renders TNBC dependent on fatty acids for mitochondrial respiration. Indeed, engagement of fatty acid oxidation, but not glycolysis, is required for LDL-induced migration and mitochondrial remodeling. Moreover, LDL induced reactive oxygen species (ROS) production by TNBC cells. 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.