A Nature Communications study identified a subpopulation of tight-junction–high, CDH17‑positive colorectal tumor cells as principal drivers of liver metastasis, reporting functional and molecular features that distinguish metastatic instigators from non-metastatic cells. The researchers used lineage tracing, single‑cell profiling and in vivo models to show that CDH17+ cells possess enhanced survival and colonization capacity in the hepatic microenvironment. The finding delineates a targetable cellular subset that could inform metastasis-directed therapies and diagnostic markers. Translational teams should evaluate whether CDH17 expression stratifies patients at high risk for liver spread and whether interventions can selectively ablate or reprogram these metastatic founder cells.