Most cancer deaths are caused by distant metastasis, in which cancer cells spread to other parts of the body. Cancers that do not metastasize are almost always curable because they can be surgically removed. Yet little is known about the mechanisms that allow cancer cells to spread to other parts of the body. Distant metastasis is a very inefficient process in which most cancer cells that enter the blood die before they are able to form metastatic tumors, but it has not been understood why. We discovered that the metastasis of melanoma cells is limited by oxidative stress, caused by the generation of highly reactive molecules, called reactive oxygen species, as a result of metabolic reaction...

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Most cancer deaths are caused by distant metastasis, in which cancer cells spread to other parts of the body. Cancers that do not metastasize are almost always curable because they can be surgically removed. Yet little is known about the mechanisms that allow cancer cells to spread to other parts of the body. Distant metastasis is a very inefficient process in which most cancer cells that enter the blood die before they are able to form metastatic tumors, but it has not been understood why. We discovered that the metastasis of melanoma cells is limited by oxidative stress, caused by the generation of highly reactive molecules, called reactive oxygen species, as a result of metabolic reactions inside cancer cells. Most melanoma cells that enter the blood die from oxidative stress. The rare melanoma cells that survive undergo metabolic adaptations that allow them to withstand oxidative stress.

Melanomas often metastasize regionally through lymph nodes before metastasizing to distant sites, like the liver. We recently discovered that when melanoma cells travel through the lymphatic system they are protected from oxidative stress, partly by oleic acid, a monounsaturated fatty acid (MUFA) that is abundant in lymph. By incorporating this MUFA into cell membranes, melanoma cells displace polyunsaturated fatty acids (PUFA), which sensitize cells to a form of cell death called ferroptosis, marked by the accumulation of oxidized lipids. During ferroptosis, PUFAs can be oxidized while MUFAs cannot due to their chemical structures. We hypothesize that by manipulating the way melanoma cells process fatty acids or by providing cells with increased PUFAs in the diet, we can increase PUFA abundance in melanoma cells and sensitize them to ferroptosis, inhibiting disease progression. By better understanding the role of lipid metabolism in metastasis we hope to develop new therapies that prevent metastasis by exacerbating oxidative stress.

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