Mediator Subunit MED4 Enforces Metastatic Dormancy in Breast Cancer (ATAC-seq_shMed1)

Breast cancer metastatic relapse after a latency period, known as metastatic dormancy, involves dormant tumor cells within pre-metastatic niches. Through rigorous genetic screening in mice, we identified the mediator complex subunit 4 gene, Med4, as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation. Med4 downregulation effectively awakened dormant breast cancer cells, prompting reactivation and macroscopic metastatic outgrowth in the lungs. Med4 depletion results in profound changes in nuclear size and three-dimensional (3D) chromatin architecture from compacted to relaxed states in contrast to the known canonical function of the Mediator complex. These changes rewire the expression of extracellular matrix (ECM) proteins, integrins, and signaling components resulting in integrin-mediated mechano-transduction and activation of YAP and MRTF. In parallel, assembly of stress fibers pulls on the nuclear membrane, and thereby contributes to mediating and reinforcing the overall chromatin modifications that occur subsequent to Med4 depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reduced MED4 expression correlates with worse prognosis. Our findings unveil a unique function of MED4 and identify an innovative mechanism by which MED4 regulates the epigenetic control of integrin signaling, pivotal in the metastatic reactivation of breast cancer. Additionally, we propose MED4 and related gene signatures as novel biomarkers for stratifying patients prone to recurrence, thus identifying subsets of patients who will benefit from targeting effectors activated by MED4 loss.