Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer

Abstract

Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. We employed single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identified pre-existing and treatment-persistent cell subpopulations that possess transcriptional stem-like features and regenerative potential when subjected to treatment. We found distinct chromatin landscapes associated with enzalutamide treatment and resistance that were linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent stem-like cells were able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal hitherto unrecognized molecular predictors of treatment response. This suggests that the high analytical resolution of pre-clinical models enabled by single-cell methods may powerfully inform clinical decision-making.

Phenotype plasticity and altered sensitivity to chemotherapeutic agents in aggressive prostate cancer cells

“…Since muscle invasive PCa is a heterogenous population of epithelial cells, with different tumor cell phenotypes appearing as a unit of epithelial-to-mesenchymal cooperation (Harryman et al, 2022), the success of HDACs as therapeutic agents may rely on understanding these complex tumor phenotypes and iHDAC mechanisms (McClure et al, 2018). This point is underscored by recent work reporting transcriptomic remodeling occurring during PCa progression as detected by single cell sequencing (Chen et al, 2021) and the persistence of specialized phenotypes associated with recurrent disease (Taavitsainen et al, 2021). We find that bleomycin, a known compound for inducing DNA-DSB (Truxova et al, 2017), exhibited a potency against the DU145 J7 cell population.…”