Matched sampling reveals uncoupled phenotypic plasticity during metastasis formation in uveal melanoma

While genetic and epigenetic evolution has been studied using primary or metastatic tumors, the transcriptomic relationship between matched pairs remains poorly understood. We performed comprehensive gene expression profiling of paired primary (pUM) and metastatic (mUM) samples to define phenotypic divergence during progression.

Two principal molecular subtypes were identified in both entities; however, matched pUM–mUM pairs showed little transcriptional concordance, indicating extensive reprogramming during metastasis. Approximately half of pUM samples exhibited a proliferative, MAPK/PI3K-driven phenotype, suggesting heterogeneous dependency on PKC signaling. Immune subtypes also diverged between sites, with pUM dominated by adaptive immune responses, whereas mUM displayed innate immune signaling and macrophage-driven immunosuppression.