Unmasking Cellular Plasticity from Development to Cancer by Lineage Tracing

Cellular plasticity, a hallmark of normal development, is frequently co-opted by cancers to drive heterogeneity, metastasis, and therapy resistance. Deciphering these dynamic processes requires lineage-tracing technologies capable of recording cellular ancestry. This review outlines the methodological evolution from widely used site-specific recombinase tools to high-resolution, single-cell DNA barcoding. The integration of lineage tracing with single-cell multiomics and spatial transcriptomics now enables the construction of dynamic atlases that link cellular history to molecular state and microenvironment. Key insights reshaping cancer biology include the frequent polyclonal origin of early lesions followed by Darwinian selection toward monoclonal dominance, the revelation that cancer stem cells represent dynamic and plastic states rather than fixed entities, and the identification of specific cellular states critical for metastasis. This synergistic framework provides a powerful means to delineate the rules of tumor evolution, opening new avenues for predicting cell fates and designing strategies to target the roots of malignancy.