Journal Article

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

Xu, Reid, Shi, Yi, Stein-O’Brien, Genevieve, Doctorman, Steven, Zhang, Jingyuan, Godet, Inês, Oza, Harsh H., Gilkes, Daniele M., Johnson, Jeanette, Santa-Maria, Cesar A., Talluri, Swathi, Considine, Michael, Kagohara, Luciane T., Weinstein, Alyssa G., Mbulaiteye, Delma, Joe, Natalie S., Fertig, Elana J.

2024

Overview

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. Hypoxia is associated with metastasis and mortality. Here, the authors show that intratumoral hypoxia is linked to oxidative stress driving both HIF and NF-kB signaling to sustain a ROS-resistant phenotype that drives metastasis partially via MUC1-C.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 14/10 / 14/19 / 14/34 / 14/35 / 14/69 / 38 / 45/29 / 45/44 / 45/91 / 631/67/1347 / 631/67/2321 / 631/67/322 / Animal models / Animals / Biopsy / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell culture / Cell death / Cell Hypoxia / Cell Line, Tumor / Clonal deletion / Female / Gene Expression Regulation, Neoplastic / Genes / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia - metabolism / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / In vivo methods and tests / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Lung Neoplasms - secondary / Metastases / Metastasis / Mice / Mortality / Mucin-1 - genetics / Mucin-1 - metabolism / multidisciplinary / Neoplasm Metastasis / Neoplastic Cells, Circulating - metabolism / Neoplastic Cells, Circulating - pathology / NF-κB protein / Oxidation resistance / Oxidative stress / Oxygen / Oxygen - metabolism / Phenotypes / Reactive oxygen species / Reactive Oxygen Species - metabolism / Science / Science (multidisciplinary) / Solid tumors / Superoxide dismutase / Transcription Factor RelA - metabolism / Transcriptomics / Tumor cells / Tumors / Xenotransplantation