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

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, Genevieve Stein-O’Brien, Luciane T. Kagohara, Cesar A. Santa-Maria, Elana J. Fertig and Daniele M. Gilkes ()
Additional contact information
Inês Godet: The Johns Hopkins University School of Medicine
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
Alyssa G. Weinstein: The Johns Hopkins University School of Medicine
Jeanette Johnson: The Johns Hopkins University School of Medicine
Michael Considine: The Johns Hopkins University School of Medicine
Swathi Talluri: The Johns Hopkins University School of Medicine
Jingyuan Zhang: The Johns Hopkins University School of Medicine
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
Luciane T. Kagohara: The 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
Daniele M. Gilkes: The Johns Hopkins University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51995-2

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