Lymph protects metastasizing melanoma cells from ferroptosis

Abstract

Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood ^{1– 4} ; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with patient-derived melanomas and immunocompetent mice with mouse melanomas had more melanoma cells per microliter of tumor-draining lymph than tumor-draining blood. Cells metastasizing through blood, but not lymph, became dependent on the ferroptosis inhibitor GPX4. Cells pre-treated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid, and less free iron, in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumors. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than melanoma cells from subcutaneous tumors. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.

One sentence summary

Lymph protects melanoma cells from the oxidative stress and ferroptotic cell death that occurs in the blood during metastasis.