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

Autor:	Godet I; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.; Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA., Oza HH; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Shi Y; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Joe NS; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Weinstein AG; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Biochemistry and Molecular Biology Program, The Johns Hopkins University School of Public Health, Baltimore, MD, USA., Johnson J; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Considine M; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Talluri S; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Zhang J; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Biochemistry and Molecular Biology Program, The Johns Hopkins University School of Public Health, Baltimore, MD, USA., Xu R; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA., Doctorman S; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA., Mbulaiteye D; NIDDK STEP-UP Program, National Institutes of Health, Bethesda, USA., Stein-O'Brien G; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Kagohara LT; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Santa-Maria CA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Fertig EJ; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA., Gilkes DM; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. dgilkes1@jhu.edu.; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA. dgilkes1@jhu.edu.; Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA. dgilkes1@jhu.edu.; Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. dgilkes1@jhu.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Sep 28; Vol. 15 (1), pp. 8416. Date of Electronic Publication: 2024 Sep 28.
DOI:	10.1038/s41467-024-51995-2
Abstrakt:	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).)
Databáze:	MEDLINE
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