Clonal lineage tracing reveals distinct invasive subpopulations in triple-negative breast cancer

The field lacks experimental systems capable of simultaneously tracking clonal identity and transcriptional state of invasive subpopulations. Here, we apply a clonal lineage-tracing platform coupled with single-cell RNA sequencing, to resolve how subpopulations contribute to invasion in a model of TNBC.

We demonstrate that invasion is driven by a subset of recurrent clones, indicating the presence of pre-existing subpopulations intrinsically primed for migratory behavior. Transcriptomic profiling further reveals two transcriptomically distinct invasive cell-states that remain stable across independent selections. Targeted perturbations suppress these dominate invasive programs but enable invasion by alternative rare clones, demonstrating compensatory clonal dynamics in response to selective pressure.