Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C
- PMID: 39341835
- PMCID: PMC11438863
- DOI: 10.1038/s41467-024-51995-2
Hypoxia induces ROS-resistant memory upon reoxygenation in vivo promoting metastasis in part via MUC1-C
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.
© 2024. The Author(s).
Conflict of interest statement
C.A.S. has received research funds from AstraZeneca, GSK/Tesaro, Merck, Gilead, Celldex, BMS, and Pfizer and has received consulting fees from Seattle Genetics. E.J.F. serves on the Scientific Advisory Board of Resistance Bio and is a consultant for Merck and Mestag Therapeutics and received research funding from Abbvie, Inc. and Roche/Genentech. The other authors have no competing interests to disclose.
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References
-
- Vaupel, P., Höckel, M. & Mayer, A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal9, 1221–1236 (2007). - PubMed
-
- Hecht, F. et al. The role of oxidative stress on breast cancer development and therapy. Tumor Biol.37, 4281–4291 (2016). - PubMed
-
- Marshall, C., Mamary, A. J., Verhoeven, A. J. & Marshall, B. E. Pulmonary artery NADPH-oxidase Is activated in hypoxic pulmonary vasoconstriction. Am. J. Respir. Cell Mol. Biol.15, 633–644 (1996). - PubMed
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