Progressive Plasticity Drives Therapy Resistance in Metastatic Colorectal Cancer

This study uncovers how phenotypic plasticity fuels the progression and therapy resistance of metastatic colorectal cancer. While primary tumors primarily exhibit LGR5+ intestinal stem-like states, metastatic tumors undergo a reprogramming process into a fetal progenitor state, followed by differentiation into non-canonical squamous and neuroendocrine-like states. These transitions, exacerbated by chemotherapy, correlate with poor patient survival. Using matched patient-derived organoids, researchers demonstrated that metastatic cells possess enhanced multilineage differentiation potential, driven by microenvironmental cues, compared to lineage-restricted primary tumor cells. The study also identifies PROX1 as a critical regulator, whose downregulation permits this reprogramming, highlighting a potential therapeutic target to curb metastatic plasticity and improve outcomes.