IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v585y2020i7823d10.1038_s41586-020-2623-z.html
   My bibliography  Save this article

Lymph protects metastasizing melanoma cells from ferroptosis

Author

Listed:
  • 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
    University of Texas Southwestern Medical Center)

  • Sean J. Morrison

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • 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 & Zhiy, 2020. "Lymph protects metastasizing melanoma cells from ferroptosis," Nature, Nature, vol. 585(7823), pages 113-118, September.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7823:d:10.1038_s41586-020-2623-z
    DOI: 10.1038/s41586-020-2623-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2623-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-2623-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Giovanni Tosi & Alessandro Paoli & Gaia Zuccolotto & Emilia Turco & Manuela Simonato & Daniela Tosoni & Francesco Tucci & Pietro Lugato & Monica Giomo & Nicola Elvassore & Antonio Rosato & Paola Cogo , 2024. "Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    3. Mihee Oh & Seo Young Jang & Ji-Yoon Lee & Jong Woo Kim & Youngae Jung & Jiwoo Kim & Jinho Seo & Tae-Su Han & Eunji Jang & Hye Young Son & Dain Kim & Min Wook Kim & Jin-Sung Park & Kwon-Ho Song & Kyoun, 2023. "The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Odeta Meçe & Diede Houbaert & Maria-Livia Sassano & Tania Durré & Hannelore Maes & Marco Schaaf & Sanket More & Maarten Ganne & Melissa García-Caballero & Mila Borri & Jelle Verhoeven & Madhur Agrawal, 2022. "Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Shunli Fu & Lili Chang & Shujun Liu & Tong Gao & Xiao Sang & Zipeng Zhang & Weiwei Mu & Xiaoqing Liu & Shuang Liang & Han Yang & Huizhen Yang & Qingping Ma & Yongjun Liu & Na Zhang, 2023. "Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:585:y:2020:i:7823:d:10.1038_s41586-020-2623-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.