Journal article
Lymph protects metastasizing melanoma cells from ferroptosis
Nature (London), Vol.585(7823), pp.113-118
09/2020
DOI: 10.1038/s41586-020-2623-z
PMCID: PMC7484468
PMID: 32814895
Abstract
Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood
; 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.
Details
- Title: Subtitle
- Lymph protects metastasizing melanoma cells from ferroptosis
- Creators
- Jessalyn M Ubellacker - The University of Texas Southwestern Medical CenterAlpaslan Tasdogan - The University of Texas Southwestern Medical CenterVijayashree Ramesh - The University of Texas Southwestern Medical CenterBo Shen - The University of Texas Southwestern Medical CenterEvann C Mitchell - The University of Texas Southwestern Medical CenterMisty S Martin-Sandoval - The University of Texas Southwestern Medical CenterZhimin Gu - The University of Texas Southwestern Medical CenterMichael L McCormick - University of IowaAlison B Durham - University of MichiganDouglas R Spitz - University of IowaZhiyu Zhao - The University of Texas Southwestern Medical CenterThomas P Mathews - The University of Texas Southwestern Medical CenterSean J Morrison - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.585(7823), pp.113-118
- DOI
- 10.1038/s41586-020-2623-z
- PMID
- 32814895
- PMCID
- PMC7484468
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- P30 ES005605 / NIEHS NIH HHS U01 CA228608 / NCI NIH HHS P01 CA217797 / NCI NIH HHS F32 HL139016 / NHLBI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 09/2020
- Academic Unit
- Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984312985902771
Metrics
24 Record Views