Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche
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 fema...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56347-2 |
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| author | Jayanta Mondal Junfeng Zhang Feng Qing Shunping Li Dhiraj Kumar Jason T. Huse Filippo G. Giancotti |
| author_facet | Jayanta Mondal Junfeng Zhang Feng Qing Shunping Li Dhiraj Kumar Jason T. Huse Filippo G. Giancotti |
| author_sort | Jayanta Mondal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7761da8717de416d842c4ddb0043e5ec |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7761da8717de416d842c4ddb0043e5ec2025-02-09T12:45:20ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-025-56347-2Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive nicheJayanta Mondal0Junfeng Zhang1Feng Qing2Shunping Li3Dhiraj Kumar4Jason T. Huse5Filippo G. Giancotti6Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer CenterDepartment of Cancer Biology, The University of Texas MD Anderson Cancer CenterGuangzhou National Laboratory, Guangzhou International Bio IslandGuangzhou National Laboratory, Guangzhou International Bio IslandCancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New YorkDepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer CenterCancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New YorkAbstract 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.https://doi.org/10.1038/s41467-025-56347-2 |
| spellingShingle | Jayanta Mondal Junfeng Zhang Feng Qing Shunping Li Dhiraj Kumar Jason T. Huse Filippo G. Giancotti Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche Nature Communications |
| title | Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| title_full | Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| title_fullStr | Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| title_full_unstemmed | Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| title_short | Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| title_sort | brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche |
| url | https://doi.org/10.1038/s41467-025-56347-2 |
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