ArticleMolecular cancer2026
Clonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance.
Article in Molecular cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- TFAP2A links drug resistance to antitumor immunity.bioRxiv : the preprint server for biology · 2026Article
- Single-cell lineage tracing maps clonal and transcriptional dynamics in melanoma metastasis.bioRxiv : the preprint server for biology · 2026Article
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Abstract
backgroundMost advanced melanomas initially respond to targeted therapy but eventually relapse. Increasing evidence suggests that drug-tolerant persister cells can adopt a reversible drug-refractory state and represent a key driver of therapeutic resistance.
methodsWe developed MeRLin, a lineage tracing platform that integrates cellular barcoding, single-cell transcriptomic profiling, RNA fluorescence in situ hybridization, and computational analyses to track clonal and transcriptional dynamics in a patient-derived melanoma model during prolonged targeted therapy. Longitudinal analyses enabled the characterization of clonal fates, transcriptional states, and spatial organization of persister populations.
resultsClonal dynamics showed that persister subpopulations initially responded to therapy, persisted through minimal residual disease, and expanded during tumor recurrence. Four persister-associated transcriptional states characterized by stress-like, lipid metabolism, PI3K signaling, and extracellular matrix remodeling programs were associated with persister populations arising from minor pre-treatment subpopulations under sustained drug pressure. Spatial transcriptomic analyses revealed structured spatial organization of these programs and suggested coordinated autocrine and paracrine interactions among persister states. Targeted barcode RNA fluorescence in situ hybridization enabled spatial mapping of clonal identity and gene expression, revealing in situ co-localization of a dominant resistant clone marked by SLC2A1 expression.
conclusionsTogether, MeRLin provides a robust framework for dissecting cancer heterogeneity and characterizing persister subpopulations. Our findings demonstrate that melanoma recurrence is associated with diverse, spatially organized persister states linked to adaptive transcriptional programs.
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