Adherent-to-suspension transition modulates circulating tumor cell dynamics and metastatic potential in melanoma

Melanoma metastasis involves dynamic cellular reprogramming that enables tumor cells to survive detachment and disseminate to distant organs. We investigated the role of adherent-to-suspension transition (AST) in melanoma metastasis, examining its dynamics during metastatic dissemination and its relationship with epithelial-to-mesenchymal-like transition (EMT-like transition). Our findings reveal that AST genes, IKZF1, IRF8, and NFE2, critically modulate anchorage dependence through the regulation of cell adhesion and survival pathways. AST gene expression exhibits dynamic plasticity throughout the metastatic cascade, peaking in circulating tumor cells and reverting in established metastases. Clonal phylogenetic reconstruction reveals that AST-high circulating tumor cell clones possess enhanced metastatic capacity and dominate distant lesions. Notably, AST enhances metastatic capabilities and invasiveness in melanoma independently of EMT-like transition. Spatial analysis further indicated that AST-positive tumor cells preferentially localize near blood vessels, suggesting a facilitating role in blood-borne metastasis. These findings provide new insights into the mechanisms driving melanoma metastasis and highlight AST as a key factor contributing to tumor cell plasticity and dissemination.