Patient-Derived Tumor Organoids to Model Cancer Cell Plasticity and Overcome Therapeutic Resistance

Cancer cell plasticity, defined as the ability of tumor cells to reversibly adopt distinct functional states, plays a central role in tumor heterogeneity, therapy resistance, and disease relapse. This process enables cells to enter stem-like, dormant, or drug-tolerant persister states in response to treatment or environmental stress without undergoing genetic changes. Such reversible transitions complicate and limit current treatments. Conventional cancer models often fail to capture the complexities of these adaptive states. In contrast, patient-derived tumor organoids (PDOs), which retain the cellular diversity and structure of primary tumors, provide a unique system for investigating plasticity. This review describes how PDOs can model cellular plasticity, such as the emergence of drug-tolerant persister cells and the interconversion between cancer stem cell states across multiple tumor types. We particularly focused on colorectal cancer organoids, for which research on the mechanism of plasticity is the most advanced. Combined with single-cell analysis, lineage tracing, and functional assays, PDOs can help identify the molecular pathways that control plasticity. Understanding these mechanisms is important for developing therapies to prevent treatment failure and control disease progression.