Adherent-to-Suspension Transition: From CTC Biology to
Anti-metastatic Therapy
Hyun Woo (Henry) Park
Department of Biochemistry, Yonsei University, Seoul, Republic of Korea
Metastasis requires solid tumor cells to overcome a fundamental anchorage paradox. They must detach from tissue architecture, survive in circulation as circulating tumor cells (CTCs), and subsequently reacquire anchorage to colonize distant organs. We recently established Adherent-to-Suspension Transition (AST) as a new paradigm in metastasis biology. AST is driven by a defined set of hematopoietic transcription factors aberrantly co-opted by solid tumor cells, enabling them to reprogram anchorage dependency and acquire CTC-like traits.
Here I will discuss how AST provides an anchorage-centric framework to address unresolved questions in metastatic dissemination. We identiy CTC precursors, or pre-CTCs, which show dynamic AST factor oscillation in less-fit tumor cells during cell competition within primary tumors. These cells exhibit early metastatic features and interact with tumor microenvironment to support immune evasion. Pre-CTCs promoted collective invasion and intravasation by facilitating vascular mimicry of neighboring tumor cells. AST is mechanistically distinct and independent of EMT. Here, we found that SMAD4 deletion accelerates AST-mediated dissemination in PDAC, providing new insight into the controversial role of TGFβ–SMAD4–EMT axis in metastasis.
AST factors enable CTCs to evade therapy-induced senescence and acquire drug resistance. Using the first multiregional single-cell transcriptomic profiling of matched primary tumors, CTCs, and metastatic lesions from patients with de novo metastatic cancers, we define AST-driven anchorage plasticity as a conserved mechanism in metastasis. Moreover, we validate AST factors as predictive biomarkers of metastatic progression and pioneer AST inhibitors as anti-metastatic therapy that suppress CTC formation and metastatic spread in preclinical models.
Together, these findings establish AST as a framework for understanding how solid tumor cells acquire hematopoietic-like traits, enter and survive in circulation, and progress through the metastatic cascade. By placing CTC biology and anchorage plasticity at the center of metastasis research, AST shifts the therapeutic focus beyond primary tumors toward preventive intervention against metastatic dissemination.
