Spider Peptides Exploit Cholesterol Levels to Target Melanoma

Spider venom might sound frightening, but for melanoma cells, it could represent a potent new threat. Researchers have identified that gomesins—peptides originally derived from spiders—possess a remarkable ability to hunt down and destroy skin cancer cells. Their precision comes from targeting a specific composition of phospholipids in the cell membrane.

The study reveals that the effectiveness of these peptides is tightly linked to lipid metabolism, particularly the glycosphingolipid pathway. Through the inhibition of a gene known as ST3GAL5, gomesins disrupt the cancer cell's outer wall, leading to cytotoxicity, or cell death. This mechanism was confirmed using advanced techniques, including CRISPR/Cas9 screening and xenograft animal studies.

A fascinating twist involves the role of cholesterol. Melanoma cells typically harbour lower cholesterol levels than healthy cells, such as neonatal foreskin fibroblasts. The research demonstrates that gomesins take advantage of this deficiency. When cholesterol is artificially added, the peptides become less effective; conversely, when cholesterol is sequestered or restricted, the peptides’ lethal impact increases.

The researchers propose that gomesins bind to specific regions called CRAC domains, restricting intracellular cholesterol and destabilising the cell. This study highlights how the unique lipid profile of melanoma can be turned against itself, paving the way for novel strategies in targeted cancer therapies.