Melanoma’s secret weapon ‘APOE’ fights death by lipid peroxidation

Researchers from the team of Prof. Patrizia Agostinis (VIB-KU Leuven) have found that melanoma cell populations protect themselves from a form of cell death called ferroptosis by secreting the lipoprotein apolipoprotein E (ApoE). Their work appears in Science Advances.

Death by lipid peroxidation

Ferroptosis is a recently discovered form of cell death. As the name implies, it is driven by iron-dependent oxidation of specific polyunsaturated lipids (PUFAs). Interestingly, drug-tolerant and metastasis-initiating cancer cells are particularly sensitive to ferroptosis.

Understanding the mechanisms that can make cancer cells resistant to ferroptosis is critical to leverage its potential in cancer treatment. Sanket More from the team of Prof. Patrizia Agostinis (VIB-KU Leuven Center for Cancer Biology) found that the more ApoE melanoma cells secrete, the less the population of metastasis-initiating melanoma cells are susceptible to treatments that induce iron-dependent cell death.

Neutralizing effects of ApoE

When ApoE is delivered to metastatic cells, it neutralizes lipids that would rapidly ‘burn’ and destroy cell membranes when ferroptosis is initiated and the ApoE increases the cellular antioxidant capacity. Combined, these ApoE effects protect melanoma cells from lysis, which reduces the therapeutic efficacy of ferroptosis in vivo.

These new insights into how melanoma cells shield themselves from ferroptosis identify the APOE gene as a critical anti-ferroptosis factor in melanoma. Since APOE4 is the greatest genetic risk factor for late-onset Alzheimer's Disease (AD), this study in melanoma informs of the complexity of ApoE biology, opening future possibilities for manipulation of this lipoprotein to modulate ferroptosis vulnerability in these devastating diseases.