biostudies-literatureUnknownLi HNCI NIH HHSMost advanced melanomas initially respond to targeted therapy but eventually relapse. Rather than acquiring new mutations, resistance is driven by drug-tolerant persister cells that enter a reversible drug-refractory state. We developed MeRLin, a high-resolution lineage tracing platform integrating cellular barcoding, single-cell transcriptomics, RNA fluorescence in situ hybridization (FISH), and computational analyses to track clonal and transcriptional dynamics in patient-derived melanoma models during prolonged therapy. Clonal dynamics revealed that persister subpopulations first responded to treatment but persisted and expanded during minimal residual disease, ultimately leading to tumor recurrence. Pre-treatment melanoma populations diversified into four conserved persister states chabioRxiv : the preprint server for biology2025.09.16.676608https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458950biostudies-literatureClonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance.PMC12458950P50 CA261608R01 CA240362U54 CA224070P01 CA114046R01 CA238237R01 CA241148Fang HHu THerlyn MBin TPatterson AJiang SBrown GSWei ZWang LMadzo JHoon DSDunne MThomas MRen JSalazar ERChen YPromi NLi HFingerman DAuslander NThacker GVillanueva JKaster JZheng QMou HLi LRaj AXiao MReale MGao LZhang XZhu XQi CfalseClonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance.Most advanced melanomas initially respond to targeted therapy but eventually relapse. Rather than acquiring new mutations, resistance is driven by drug-tolerant persister cells that enter a reversible drug-refractory state. We developed MeRLin, a high-resolution lineage tracing platform integrating cellular barcoding, single-cell transcriptomics, RNA fluorescence in situ hybridization (FISH), and computational analyses to track clonal and transcriptional dynamics in patient-derived melanoma models during prolonged therapy. Clonal dynamics revealed that persister subpopulations first responded to treatment but persisted and expanded during minimal residual disease, ultimately leading to tumor recurrence. Pre-treatment melanoma populations diversified into four conserved persister states cha2025-01-01T00:00:00Z2025 Sep2026-05-04T03:14:35.348Z2026-05-04T03:13:05.319ZS-EPMC124589504100087510.1101/2025.09.16.676608