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.

Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis

“…As another example, during the evolution of distant metastases, PDAC co-evolved a dependence on the oxidative branch of the pentose phosphate pathway through global epigenetic reprogramming of H3K9 methylation ( Figure 6 C) [ 133 ]. The mechanism by which melanoma cells tend to metastasize, initially to the lymph nodes and then to other distant organs, has recently been linked to decreased oxidative stress in the lymphatic environment ( Figure 6 C) [ 135 ]. This may be caused by higher levels of glutathione and oleic acid and lower free-iron levels in the lymph, which decrease oxidative stress and ferroptosis.…”

“…This may be caused by higher levels of glutathione and oleic acid and lower free-iron levels in the lymph, which decrease oxidative stress and ferroptosis. This ultimately contributes to protect melanoma cells from ferroptosis and increases their ability to form metastases in distant organs [ 135 ].…”

Metabolic Dynamics of In Vitro CD8+ T Cell Activation

“…Membrane lipid composition could similarly impact T cell signaling and is an interesting area for further research. Previously, it has been reported that polyunsaturated membrane lipids can cause ferroptosis in cancer cells that travel in the bloodstream, and this can be reduced in cancer cells that first travel to the lymph where they accumulate monounsaturated membrane lipids [18,19]. It is, therefore, tempting to speculate that the observed shift toward less unsaturated PCs helps to prepare for the release of effector CD8+ T cells from the spleen into the bloodstream.…”

Newcastle disease virus induced ferroptosis through p53-SLC7A11-GPX4 axis mediated nutrient deprivation in tumor cells

“…Ferroptosis, a newly discovered form of regulated cell death, involves iron and reactive oxygen species (ROS), and is characterized by the accumulation of phospholipid peroxides (Chu et al, 2019;Dixon et al, 2012;Doll et al, 2017;Jiang et al, 2015;Yang et al, 2014). The peroxidation of phospholipids and the accumulation of lipid ROS are the key drivers of ferroptosis-induced cell death (Su et al, 2019;Ubellacker et al, 2020). Ferroptosis is initiated through various pathways, including the depletion of intracellular glutathione (GSH) and lipid peroxidation, caused by increases in oxidizing iron and the labile iron pool (Cao and Dixon, 2016;Gao et al, 2019;Hadian and Stockwell, 2020;Muri et al, 2019).…”