Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer
Abstract Background Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly faci...
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2025-01-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-025-01432-w |
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| author | Luis Aparicio Laura Crowley John R. Christin Caroline J. Laplaca Hanina Hibshoosh Raul Rabadan Michael M. Shen |
| author_facet | Luis Aparicio Laura Crowley John R. Christin Caroline J. Laplaca Hanina Hibshoosh Raul Rabadan Michael M. Shen |
| author_sort | Luis Aparicio |
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| description | Abstract Background Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate. Methods We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression. Results Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states. Conclusions Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies. |
| format | Article |
| id | doaj-art-e4964a05038748c7aef28b9fd6f678b7 |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Genome Medicine |
| spelling | doaj-art-e4964a05038748c7aef28b9fd6f678b72025-01-19T12:33:57ZengBMCGenome Medicine1756-994X2025-01-0117112210.1186/s13073-025-01432-wMeta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancerLuis Aparicio0Laura Crowley1John R. Christin2Caroline J. Laplaca3Hanina Hibshoosh4Raul Rabadan5Michael M. Shen6Program for Mathematical Genomics, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Systems Biology, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Systems Biology, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Systems Biology, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and SurgeonsProgram for Mathematical Genomics, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Systems Biology, Columbia University Vagelos College of Physicians and SurgeonsAbstract Background Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate. Methods We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression. Results Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states. Conclusions Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies.https://doi.org/10.1186/s13073-025-01432-wProstate cancerScRNA-seqTumor heterogeneityPlasticityCastrationAndrogen receptor |
| spellingShingle | Luis Aparicio Laura Crowley John R. Christin Caroline J. Laplaca Hanina Hibshoosh Raul Rabadan Michael M. Shen Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer Genome Medicine Prostate cancer ScRNA-seq Tumor heterogeneity Plasticity Castration Androgen receptor |
| title | Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer |
| title_full | Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer |
| title_fullStr | Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer |
| title_full_unstemmed | Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer |
| title_short | Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer |
| title_sort | meta analyses of mouse and human prostate single cell transcriptomes reveal widespread epithelial plasticity in tissue regression regeneration and cancer |
| topic | Prostate cancer ScRNA-seq Tumor heterogeneity Plasticity Castration Androgen receptor |
| url | https://doi.org/10.1186/s13073-025-01432-w |
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