Mitochondrial Metabolism Drives Low-density Lipoprotein-induced Breast Cancer Cell Migration

Area of Science:

• Oncology
• Metabolic pathways
• Cancer cell biology

Background:

• Metastasis is a primary cause of cancer mortality.
• Lipid-rich environments, including high low-density lipoprotein (LDL) cholesterol, promote breast cancer metastasis.
• The role of mitochondrial metabolism in triple-negative breast cancer (TNBC) metastasis within lipid-enriched settings is unclear.

Purpose of the Study:

• To investigate how LDL influences TNBC cell migration and invasion.
• To elucidate the role of mitochondrial metabolism in LDL-induced TNBC metastasis.
• To identify potential therapeutic targets for preventing TNBC metastasis.

Main Methods:

• Cell culture and *in vivo* models of TNBC.
• Assessment of cell migration, invasion, and lipid droplet formation.
• Mitochondrial mass, network analysis, and metabolic profiling (transcriptomic and energetic analyses).
• Inhibition of CD36 and reactive oxygen species (ROS) pathways.

Main Results:

• LDL increased lipid droplet accumulation, CD36 expression, and TNBC cell migration and invasion.
• LDL enhanced mitochondrial mass and network spread in migrating cells, dependent on actin remodeling.
• TNBC cells became reliant on fatty acid (FA) oxidation for mitochondrial respiration under LDL influence.
• LDL-induced migration and mitochondrial remodeling required FA transport into mitochondria.
• Mitochondrial accumulation of long-chain fatty acids and increased ROS production were observed upon LDL treatment.
• Blocking CD36 or ROS abrogated LDL-induced cell migration and metabolic reprogramming.

Conclusions:

• LDL promotes TNBC cell migration and invasion by reprogramming mitochondrial metabolism towards fatty acid utilization.
• CD36 and ROS are critical mediators of LDL-induced mitochondrial adaptations and cell migration.
• Targeting CD36 or ROS presents a potential antimetastatic strategy for TNBC in lipid-rich environments.