Tracing back primed resistance in cancer via sister cells

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods coupling cell states to future fates. However, transcriptional changes that drive pre-treatment cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance, and allows identification of asymmetric features that drive phenotypic heterogeneity. Applying ReSisTrace in ovarian cancer cells revealed that BRCAness transcriptional signatures are associated with pre-existing vulnerability not only to olaparib and carboplatin treatments, but also to natural killer cell-mediated cytotoxicity. This novel connection between DNA repair defect and susceptibility to natural killer cells was further validated both functionally and in a clinical cohort. The high-resolution analysis by ReSisTrace enables resolving pre-existing transcriptional features of treatment vulnerability, facilitating molecular patient stratification for personalised therapies.