Lymph protects metastasizing melanoma cells from ferroptosis
By Jessalyn M. Ubellacker, Alpaslan Tasdogan, V. Ramesh, Bo Shen, Evann C Mitchell, Misty S. Martin-Sandoval, Zhimin Gu, M. McCormick, Alison B Durham, D. Spitz and 3 more. Nature, 2020
765 citations recorded by the source corpus.
Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood1–4; 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 melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated 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 tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood. Melanoma cells undergo less oxidative stress and less ferroptosis in lymph than in blood, owing to higher levels of oleic acid in lymph, and thus exposure to the lymphatic environment increases subsequent metastasis through blood.
Subfields: Cancer Research, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/7315a6ded34f10e84200a30ec7a8833f3ed83f44
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Citations in the corpus
- Ferroptosis: mechanisms and links with diseases (2021, background): “It is recently shown that the lymphatic environment protects metastasizing melanoma cells from ferroptosis to increase their survival rate during subsequent metastasis through blood.(183) By pretreating with ferroptosis inhibitors, the melanoma cells can form more metastases than untreated cells aft”
- Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “revealed that melanoma cells prefer to form more metastases through the lymphatic system than through the blood to avoid ferroptosis [11].”
- The cell biology of ferroptosis (2024, neutral): “ACSL4 and ACSL3 appear generally to function in opposition, with ACSL4-driven PUFA metabolism increasing fer-roptosis sensitivity and ACSL3-dependent MUFA metabolism promoting ferroptosis resistance 24,28,30,99,105,106 .”
- Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “This compositional difference contributes to decreased oxidative stress in lymph and inhibits the ferroptotic death of melanoma cells [139].”
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “54 ACSL3 converts MUFAs into their acyl-CoA esters, facilitating their incorporation into membrane PLs. 141 Thus, similar to PUFAs, MUFAs need to be inserted into the membrane to exhibit antioxidant properties.”