During metastatic progression, circulating cancer cells become lodged within the microvasculature of end-organs, where a majority die from mechanical deformation. Though this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing (RNA-seq) technology to isogenic cancer cells of differing metastatic capacity, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1 1–89, as recurrently enriched in highly metastatic breast cancer cells. PANX1 1–89 functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis via P2y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival upon microvasculature-induced biomechanical trauma.