A specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during the metastatic cascade remains elusive. Using multi-omics approaches in liquid biopsy, we discovered a biological phenomenon referred to as Adherent-to-Suspension Transition (AST) that reprograms adherent cells into suspension cells via aberrant induction of hematopoietic transcriptional regulators, IKZF1, NFE2, BTG2, and IRF8, which are hijacked by solid tumor cells to disseminate into CTCs. During dissemination, tumor microenvironment triggers the epigenetic alteration of AST factors in the invasive front of solid tumors to evoke spontaneous cell-matrix dissociation, acquire anoikis resistance, and bypass immune surveillance of CTCs, however, in the absence of lineage differentiation and EMT. By performing scRNAseq in a cohort of de novo metastatic breast cancer patients, which consists tissue- and liquid biopsy paired specimens of primary tumor, CTCs, and metastatic lesions, we uncovered how Adherent-Suspension Plasticity (ASP) regulated anchorage plasticity during the dissemination and colonization process within the metastatic cascade. Finally, we demonstrate therapeutic strategies that target AST factors to specifically abrogate CTC formation and suppress distant metastases.Together, our finding underscores the mechanism that reprograms anchorage dependency of cancer cells and highlights undescribed hematopoietic targets for the development of anti-metastatic therapy. Furthermore, ASP opens unexplored scenarios of how reprogramming anchorage dependency in diverse physiological events orchestrates development, organ morphogenesis, and immune cell activation.