Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer

Abstract

Acquired resistance to carboplatin is a major obstacle to the cure of ovarian cancer, but its molecular underpinnings are still poorly defined. We selected multiple clones derived from a single cell in parallel for similar levels of resistance to carboplatin. The resistant clones showed no significant genetic alterations, but each one activated different mechanisms of resistance resulting in transcriptional heterogeneity. Single-cell mRNA sequencing defined multiple transcriptional states associated with clone identity and resistance evolution, and identified a subset of unselected parental cells that were already in a resistant state. Six expression signatures derived from the resistant states distinguished primary from recurrent high-grade serous ovarian cancers, predicted both response and survival and disclosed functional differences between intrinsic and acquired resistance. This multidimensional, single-cell analysis offers new insights into the dynamics of the acquisition of resistance to carboplatin, a drug of major importance to the treatment of ovarian and other cancers.