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

ABSTRACT: Androgen 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, comprising both publicly available cohorts and data generated by our research team, and established the HuPSA (Human Prostate Single cell Atlas) and MoPSA (Mouse Prostate Single cell Atlas) 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+ prostate club cells and two novel lineage plastic cancerous populations, namely Progenitor-like and KRT7. Immunohistochemical staining analysis confirmed the presence of these populations in both human and mouse PCa tissues, reinforcing their significance in PCa pathobiology. Furthermore, employing HuPSA based deconvolution, we scrutinized 877 high-quality 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 projected the scRNAseq data derived from C4-2B xenograft tumors onto HuPSA. Our analysis effectively identified the diverse subpopulations within the tumor, including C4-2B derived AdPCa and NEPCa cells as well as the murine cells in the tumor microenvironment. We launched the “PCaAtlas” app (https://pcatools.shinyapps.io/ProAtlas_dev/) for users to visualize genes expression in re-classified human prostatic tissue samples. In conclusion, our study has successfully integrated multiple scRNAseq datasets and made these data easily accessible to researchers. Our results elucidate a roadmap of PCa progression, showcasing the development of heterogeneous populations and the involvement of lineage plasticity. This understanding holds promise for guiding the development of precision medicine in PCa field. Additionally, the HuPSA and MoPSA provide invaluable blueprints for analyzing and interpreting user-generated PCa single-cell RNAseq data.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE246155 | GEO | 2024/08/08

REPOSITORIES: GEO

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Project description:Background: Prostate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome-wide mRNA expression changes in PCa cells in response to Runx2. Results: We engineered a C4-2B PCa sub-line called C4-2B/Rx2dox, in which doxycycline (Dox) treatment stimulates Runx2 expression from very low levels to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer-associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal. Conclusions: The effects of Runx2 in C4-2B/Rx2dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways. C4-2B/Rx2dox cells were subjected to microarray gene expression analysis after one and two days of treatment with either Dox or vehicle in biological quadruplicates (a total of 16 samples).

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

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