Reconstructing the metastatic journey: functional circulating tumor cells and disseminated tumor cells based models for translational oncology

Metastatic progression, driven by the dissemination of circulating tumor cells (CTCs) through the bloodstream, remains the leading cause of cancer-related death. A rare subset of CTCs, characterized by tumor-initiating properties and phenotypic plasticity, plays a pivotal role in the formation of distant metastases. The ability of these cells to survive in the circulation, evade the immune surveillance, and establish secondary tumors underscores their biological significance. However, CTC extreme rarity and heterogeneity pose major challenges for their in-depth functional characterization. Disseminated tumor cells (DTCs) are cells that have extravasated and persist in distant organ niches, often in a dormant state, and represent a complementary and equally critical component of metastatic progression. Their capacity to remain quiescent for prolonged periods before reactivation highlights the need to study both CTCs and DTCs to fully understand metastasis initiation and relapse. Recent advances in CTC isolation and culture have led to the development of patient-derived CTC lines and CTC-derived xenograft animal models, offering unprecedented opportunities to investigate metastatic seeding, therapeutic resistance and tumor evolution. CTC- and DTC-based models provide valuable insights into the biology of CTCs from different cancer types, revealing key molecular drivers of metastasis formation and potential therapeutic targets. In this review, we summarize the state-of-the-art methodologies for establishing CTC- and DTC-based models and evaluate their contribution to understand tumor progression and response to treatments. We discuss the current challenges in generating and maintaining these models, including the influence of hypoxic conditions, enrichment strategies, and culture medium optimization. Then, we highlight their potential applications in precision oncology, particularly for biomarker discovery and for preclinical drug testing.