A cancer stem cell population underlies a multi-lineage phenotype and drug resistance in prostate cancer

To resist lineage-dependent therapies, cancer cells adopt a plastic stem-like state, leading to phenotypic heterogeneity. Here we dissect the cellular origins of such heterogeneity in a metastatic castration-resistant prostate cancer (CRPC) patient-derived adenocarcinoma organoid model displaying a range of luminal and neuroendocrine phenotypes and driven by mutations in cell cycle (CDKN1B) and epigenetic (ARID1A, and ARID1B) regulators. As shown by lineage tracing, metastatic tumor heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that each produced a full distribution of differentiated lineage markers, suggesting multiclonal evolution to a relatively stable bipotential state. Single cell ATAC-seq analyses revealed the co-occurrence of transcription factor activities associated with multiple disparate lineages in the stem/progenitors: WNT and RXR stem factors, AR and FOXA1 luminal epithelial drivers, and NR2F1 and ASCL1 neural factors. Inhibition of AR in combination with AURKA but not EZH2 blocked tumor growth. These data provide insight into the origins and dynamics of cancer cell plasticity and stem targeted therapy. ### Competing Interest Statement The authors have declared no competing interest.