Cancer Progression
Cancer cells hijack stem cell self-renewal mechanisms by acquiring mutations that over-activate these pathways. By comparing the mechanisms that regulate the self-renewal of normal stem cells and the self-replication of cancer cells, we identify differences that represent potential vulnerabilities that can be targeted to kill cancer cells.
We are particularly interested in the mechanisms that regulate melanoma metastasis. We discovered that the survival of melanoma cells during metastasis is limited by oxidative stress. The rare cells that survive metastasis appear to undergo metabolic changes that enhance oxidative stress resistance. By better understanding these mechanisms, we hope to develop pro-oxidant therapies that inhibit cancer progression by exacerbating the oxidative stress experienced by cancer cells.
Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood. We found that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in the blood. This is true in both patient-derived melanomas in immunocompromised mice and mouse melanomas in syngeneic, immunocompetent mice. Cells metastasizing through blood, but not lymph, appear to undergo ferroptosis, a form of cell death marked by lipid oxidation. Multiple differences between lymph and blood may contribute to this difference in oxidative stress, including higher levels of oleic acid in lymph. Oleic acid is a monounsaturated fatty acid that can protect cancer cells from ferroptosis by reducing the abundance of oxidizable polyunsaturated fatty acids in phospholipids. We found it is incorporated by melanoma cells in lymph and promotes their survival in the blood. This offers a potential explanation for a clinical behavior that is the basis for much of cancer staging and treatment—the tendency of melanomas and epithelial cancers to metastasize first through lymphatics and then through the blood.
