Lymph protects metastasizing melanoma cells from ferroptosis

Jessalyn M. Ubellacker, Alpaslan Tasdogan, Vijayashree Ramesh, Bo Shen, Evann C. Mitchell, Misty S. Martin-Sandoval, Zhimin Gu, Michael L. McCormick, Alison B. Durham, Douglas R. Spitz, Zhiyu Zhao, Thomas P. Mathews and Sean J. Morrison ()
Additional contact information
Jessalyn M. Ubellacker: University of Texas Southwestern Medical Center
Alpaslan Tasdogan: University of Texas Southwestern Medical Center
Vijayashree Ramesh: University of Texas Southwestern Medical Center
Bo Shen: University of Texas Southwestern Medical Center
Evann C. Mitchell: University of Texas Southwestern Medical Center
Misty S. Martin-Sandoval: University of Texas Southwestern Medical Center
Zhimin Gu: University of Texas Southwestern Medical Center
Michael L. McCormick: University of Iowa
Alison B. Durham: University of Michigan
Douglas R. Spitz: University of Iowa
Zhiyu Zhao: University of Texas Southwestern Medical Center
Thomas P. Mathews: University of Texas Southwestern Medical Center
Sean J. Morrison: University of Texas Southwestern Medical Center

Nature, 2020, vol. 585, issue 7823, 113-118

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (10)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2623-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:585:y:2020:i:7823:d:10.1038_s41586-020-2623-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2623-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().