A transient MXD4-dependent proliferative pause enables survival of brain micrometastases.

Successful metastatic colonization requires cancer cells to survive multiple stresses during early organ adaptation, yet how metastasis-initiating cells overcome this bottleneck remains unknown. Here, we identify a transient MXD4-dependent proliferative pause that enables aggressive cancer cells to survive early brain colonization. Before vascular co-option-associated outgrowth, metastatic cells temporarily restrain proliferation through the MYC antagonist MXD4, buffering stresses encountered after extravasation. Genetic disruption of MXD4 compromises survival of micrometastases, preventing their progression to macrometastases. Analyses of human brain micrometastases validate this transient adaptive state in patients. Exploiting vulnerabilities associated with the proliferative pause reveals preventive therapeutic opportunities across experimental settings, including spontaneous brain metastasis models and minimal residual disease following neurosurgical resection. In addition, patient-derived organotypic cultures confirm the feasibility of targeting this state with clinically available drugs. These findings uncover a previously unrecognized adaptive stage during metastatic colonization and identify actionable vulnerabilities to prevent brain metastasis progression and relapse.