2. Academic Validation
  3. Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche

Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche

  • Nat Commun. 2025 Feb 5;16(1):1378. doi: 10.1038/s41467-025-56347-2.
Jayanta Mondal # 1 2 3,  Junfeng Zhang # 4 5,  Feng Qing 6,  Shunping Li 6,  Dhiraj Kumar 7 8 9,  Jason T Huse 10 11,  Filippo G Giancotti 7 8
Affiliations

Affiliations

  • 1 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 3 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 4 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. zhang_junfeng@gzlab.ac.cn.
  • 5 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China. zhang_junfeng@gzlab.ac.cn.
  • 6 Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China.
  • 7 Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA.
  • 8 Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
  • 9 Johnson and Johnson Enterprise Innovations, Inc, Interventional Oncology, Spring House, PA, USA.
  • 10 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. jhuse@mdanderson.org.
  • 11 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. jhuse@mdanderson.org.
  • # Contributed equally.
PMID: 39910049 DOI: 10.1038/s41467-025-56347-2
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.

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