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

Mucin-1 / metabolism Humans Animals Reactive Oxygen Species / metabolism Female Cell Line, Tumor Mice Breast Neoplasms / pathology Gene Expression Regulation, Neoplastic Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Neoplastic Cells, Circulating / metabolism Lung Neoplasms / secondary Oxygen / metabolism Transcription Factor RelA / metabolism Neoplasm Metastasis Hypoxia / metabolism Cell Hypoxia

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
28 Sep 2024
Historique:
received: 10 03 2023
accepted: 21 08 2024
medline: 29 9 2024
pubmed: 29 9 2024
entrez: 28 9 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-51995-2 PMID: 39341835
pubmed: 39341835
doi: 10.1038/s41467-024-51995-2
pii: 10.1038/s41467-024-51995-2
doi:

Substances chimiques

Mucin-1 0
Reactive Oxygen Species 0
MUC1 protein, human 0
Hypoxia-Inducible Factor 1, alpha Subunit 0
Oxygen S88TT14065
Transcription Factor RelA 0
HIF1A protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

8416

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : P50CA006973

Informations de copyright

© 2024. The Author(s).

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Auteurs

Inês 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.

Harsh H Oza (HH)

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0001-6724-5975

Yi Shi (Y)

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0009-0003-6807-0048

Natalie S 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.

Alyssa G 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.
ORCID: 0000-0001-9342-0263

Jeanette 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.
ORCID: 0000-0002-8268-5335

Michael 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.

Swathi Talluri (S)

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jingyuan 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.

Reid Xu (R)

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.

Steven Doctorman (S)

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.

Delma Mbulaiteye (D)

NIDDK STEP-UP Program, National Institutes of Health, Bethesda, USA.

Genevieve 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.
ORCID: 0000-0001-8681-9110

Luciane T 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.
ORCID: 0000-0003-1706-0950

Cesar A Santa-Maria (CA)

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Elana J 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.
ORCID: 0000-0003-3204-342X

Daniele M 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.
ORCID: 0000-0003-3984-9338

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Antigènes glycanniques associés aux tumeurs › Mucine-1 › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Eucaryotes › Animaux › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Produits chimiques inorganiques › Composés de l'oxygène › Espèces réactives de l'oxygène › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Facteur-1 induit par l'hypoxie › Sous-unité alpha du facteur-1 induit par l'hypoxie › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Cellules tumorales circulantes › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Produits chimiques inorganiques › Gaz › Oxygène › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteur de transcription NF-kappa B › Facteur de transcription RelA › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Signes et symptômes respiratoires › Hypoxie › Hypoxia induces ROS-resistant memory upon...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Respiration cellulaire › Hypoxie cellulaire › Hypoxia induces ROS-resistant memory upon...