Faculty, Staff and Student Publications

Publication Date

2-5-2025

Journal

Nature Communications

Abstract

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress response T cells in lungs from female mice harboring Brd7-deficient metastases. Finally, attenuating this immunosuppressive milieu by neutrophil depletion, neutrophil extracellular trap (NET) inhibition, or immune checkpoint therapy abrogates metastatic outgrowth. These findings implicate Brd7 and PBAF in triggering metastatic outgrowth in cancer, pointing to targetable underlying mechanisms involving specific immune cell compartments.

Keywords

Animals, Female, Mice, Lung Neoplasms, Chromosomal Proteins, Non-Histone, Humans, Tumor Microenvironment, Cell Line, Tumor, Breast Neoplasms, Neutrophils, Gene Expression Regulation, Neoplastic, CD8-Positive T-Lymphocytes, Lung, Neoplasm Metastasis, Mice, Knockout, Mice, Inbred C57BL, Bromodomain Containing Proteins

DOI

10.1038/s41467-025-56347-2

PMID

39910049

PMCID

PMC11799300

PubMedCentral® Posted Date

2-5-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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