New Discoveries Reveal the Role of Iron Metabolism in Melanoma Cell Plasticity

Researchers at VIB and collaborators have unveiled a novel mechanism that enables melanoma cells to switch between two distinct states—proliferative and invasive—highlighting potential new targets for cancer therapy. This groundbreaking study, published in Nature Metabolism, emphasizes the importance of iron metabolism and organelle communication in melanoma progression.

Melanoma, known for its aggressive nature, often changes its phenotype to escape treatments and spread to other parts of the body. While past studies focused on genetic mutations driving this behavior, recent research by Prof. Patrizia Agostinis’s team shifts the focus to the cellular machinery that governs iron distribution inside cancer cells. These processes are crucial for energy production, cell survival, and metastasis.

The team discovered that melanoma cells reversibly switch between the melanocytic (MEL) state, which is more sensitive to current therapies, and a mesenchymal-like (MES) state, characterized by invasive capabilities. Specifically, MES cells exhibit disrupted iron transport between mitochondria—the energy producers—and lysosomes, organelles responsible for storing and recycling iron.

This altered iron trafficking is linked to the downregulation of BDH2, an enzyme essential for importing iron into mitochondria. Reduced BDH2 leads to iron accumulation in lysosomes, promoting the invasive phenotype. Interestingly, restoring BDH2 levels reestablishes normal iron transfer, improves mitochondrial function, and decreases susceptibility to ferroptosis—a form of iron-dependent cell death—potentially opening new avenues for targeted therapy.

This research highlights the intricate relationship between cellular metabolism and tumor plasticity. Targeting the machinery involved in organelle crosstalk and iron homeostasis may prevent melanoma progression and combat resistance. As understanding of metabolic regulation advances, it offers hope for developing innovative treatments for melanoma and other cancers exhibiting similar metabolic flexibility.

The findings underscore the significance of iron trafficking in tumor behavior and suggest that manipulating organelle communication could serve as a promising strategy against resistant cancer cell populations.