HuPSA and MoPSA Atlases Revealed Novel Cell Populations and Lineage Plasticity in Prostate Cancer at Single-Cell Level

Abstract

AbstractAndrogen deprivation therapy has improved patient survival. Nevertheless, treatment resistance inevitably emerges due to the complex interplay of tumor heterogeneity and lineage plasticity. We integrated scRNAseq data from multiple studies, including both public cohorts and data generated in our laboratory, and generated the HuPSA (HumanProstateSingle cellAtlas) and MoPSA (MouseProstateSingle cellAtlas) datasets. Through unsupervised clustering and manual annotation, we found that both atlases consisted of previously known cell clusters including prostate adenocarcinoma (AdPCa), neuroendocrine prostate cancer (NEPCa), stromal, and immune cell populations. Our analysis also unearthed the less described populations including MMP7+normal prostate club cells and two novel lineage plastic cancerous populations, namely progenitor-like and KRT7+cells. Immunohistochemical staining analysis confirmed the presence of these populations in both human and mouse PCa tissues, reinforcing their significance in PCa pathobiology. To unravel the molecular drivers of these distinct cell populations, we explored the upstream regulators of the genes enriched in these cells and found that Wnt signaling is enriched in these progenitor-like cells. Furthermore, employing HuPSA-based deconvolution, we scrutinized over one thousand human PCa bulk RNAseq samples and reclassified them into different molecular subtypes, including the newly discovered KRT7 and progenitor-like categories. Moreover, employing supervised dimensional reduction and label transferring techniques, we mapped the scRNAseq data derived from C4-2B xenograft tumors onto HuPSA. Our analysis effectively unveiled the populational heterogeneity and neuroendocrine differentiation in this C4-2B xenograft model. In conclusion, our study elucidates a roadmap of PCa progression, showcasing the development of heterogeneous populations through lineage plasticity. This understanding holds promise for guiding the development of precise medicine in PCa field. Additionally, the HuPSA and MoPSA provide invaluable blueprints for analyzing and interpreting external PCa single-cell RNAseq data.