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Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C

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Listed:
  • Inês Godet

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University
    The Johns Hopkins University)

  • Harsh H. Oza

    (The Johns Hopkins University School of Medicine)

  • Yi Shi

    (The Johns Hopkins University School of Medicine)

  • Natalie S. Joe

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Medicine)

  • Alyssa G. Weinstein

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Public Health)

  • Jeanette Johnson

    (The Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Michael Considine

    (The Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Swathi Talluri

    (The Johns Hopkins University School of Medicine)

  • Jingyuan Zhang

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Public Health)

  • Reid Xu

    (The Johns Hopkins University)

  • Steven Doctorman

    (The Johns Hopkins University)

  • Delma Mbulaiteye

    (National Institutes of Health)

  • Genevieve Stein-O’Brien

    (The Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Medicine)

  • Luciane T. Kagohara

    (The Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Cesar A. Santa-Maria

    (The Johns Hopkins University School of Medicine)

  • Elana J. Fertig

    (The Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University)

  • Daniele M. Gilkes

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University
    The Johns Hopkins University
    The Johns Hopkins University School of Medicine)

Abstract

Hypoxia occurs in 90% of solid tumors and is associated with metastasis and mortality. Breast cancer cells that experience intratumoral hypoxia are 5x more likely to develop lung metastasis in animal models. Using spatial transcriptomics, we determine that hypoxic cells localized in more oxygenated tumor regions (termed ‘post-hypoxic’) retain expression of hypoxia-inducible and NF-kB-regulated genes, even in the oxygen-rich bloodstream. This cellular response is reproduced in vitro under chronic hypoxic conditions followed by reoxygenation. A subset of genes remains increased in reoxygenated cells. MUC1/MUC1-C is upregulated by both HIF-1α and NF-kB-p65 during chronic hypoxia. Abrogating MUC1 decreases the expression of superoxide dismutase enzymes, causing reactive oxygen species (ROS) production and cell death. A hypoxia-dependent genetic deletion of MUC1, or MUC1-C inhibition by GO-203, increases ROS levels in circulating tumor cells (CTCs), reducing the extent of metastasis. High MUC1 expression in tumor biopsies is associated with recurrence, and MUC1+ CTCs have lower ROS levels than MUC1- CTCs in patient-derived xenograft models. This study demonstrates that therapeutically targeting MUC1-C reduces hypoxia-driven metastasis.

Suggested Citation

  • Inês Godet & Harsh H. Oza & Yi Shi & Natalie S. Joe & Alyssa G. Weinstein & Jeanette Johnson & Michael Considine & Swathi Talluri & Jingyuan Zhang & Reid Xu & Steven Doctorman & Delma Mbulaiteye & Gen, 2024. "Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51995-2
    DOI: 10.1038/s41467-024-51995-2
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    References listed on IDEAS

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    1. Inês Godet & Yu Jung Shin & Julia A. Ju & I Chae Ye & Guannan Wang & Daniele M. Gilkes, 2019. "Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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