Dynamic plasticity of prostate cancer intermediate cells during androgen receptor targeted therapy

The prevalence of treatment induced small cell neuroendocrine 1 prostate cancer (t-SCNC) has increased due to the use of potent AR signaling inhibitors. Understanding the kinetics and potential for reversibility of the t-SCNC lineage switch has been hampered by the lack of model systems suitable for studying intermediate tumor cell states. We define a reporter model amenable for measuring acute and dynamic transcriptional changes in response to castration or AR targeting agents. Using this approach, we have identified discreet, transcriptionally defined tumor subpopulations present in hormone intact conditions including the presence of intermediate subpopulations that are coordinately high for PSA and NSE promoter activity. In the presence of castration or AR targeting agents, intermediate cells serve a necessary and sufficient function during therapy induced conversion of human PC cells to an NE transcriptional high status. Castration can also induce greater amounts of secreted NSE suggesting a potential biomarker role. Further, we show that early treatment induced PSA-NSE transcriptional plasticity is reversible in PTEN deficient prostate cancer cells but not in context of secondary genetic driver genes such as MYCN. Castrate and FBS control single-cell samples of LNCaP cells