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
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons