Lymph protects metastasizing melanoma cells from ferroptosis

  • Nature. 2020 Sep;585(7823):113-118. doi: 10.1038/s41586-020-2623-z.
Jessalyn M Ubellacker  1 ,  Alpaslan Tasdogan  1 ,  Vijayashree Ramesh  1 ,  Bo Shen  1 ,  Evann C Mitchell  1 ,  Misty S Martin-Sandoval  1 ,  Zhimin Gu  1 ,  Michael L McCormick  2 ,  Alison B Durham  3 ,  Douglas R Spitz  2 ,  Zhiyu Zhao  1 ,  Thomas P Mathews  1  4 ,  Sean J Morrison  5  6  7
Affiliations
  • 1. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
  • 3. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
  • 4. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 7. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
PMID: 32814895 DOI: 10.1038/s41586-020-2623-z
Abstract

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.