Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells

Abstract

Human cancers are heterogeneous containing stem-like cancer cells operationally defined as cancer stem cells (CSCs) that possess great tumor-initiating and long-term tumor-propagating properties. In this study, we systematically dissect the phenotypic, functional and tumorigenic heterogeneity in human prostate cancer (PCa) using xenograft models and >70 patient tumor samples. In the first part, we further investigate the PSA^−/lo PCa cell population, which we have recently shown to harbor self-renewing long-term tumor-propagating cells and present several novel findings. We show that discordant AR and PSA expression in both untreated and castration-resistant PCa (CRPC) results in AR⁺PSA⁺, AR⁺PSA⁻, AR⁻PSA⁻, and AR⁻PSA⁺ subtypes of PCa cells that manifest differential sensitivities to therapeutics. We further demonstrate that castration leads to a great enrichment of PSA^−/lo PCa cells in both xenograft tumors and CRPC samples and systemic androgen levels dynamically regulate the relative abundance of PSA⁺ versus PSA^−/lo PCa cells that impacts the kinetics of tumor growth. We also present evidence that the PSA^−/lo PCa cells possess distinct epigenetic profiles. As the PSA^−/lo PCa cell population is heterogeneous, in the second part, we employ two PSA⁻ (Du145 and PC3) and two PSA⁺ (LAPC9 and LAPC4) PCa models as well as patient tumor cells to further dissect the clonogenic and tumorigenic subsets. We report that different PCa models possess distinct tumorigenic subpopulations that both commonly and uniquely express important signaling pathways that could represent therapeutic targets. Our results have important implications in understanding PCa cell heterogeneity, response to clinical therapeutics, and cellular mechanisms underlying CRPC.