Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states

Abstract

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.

Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

“…We used RNA velocity to infer the likely trajectories of epithelial cell differentiation (21,22). One trajectory suggested that club cells act as luminal cell progenitors, an observation previously reported in prostate cancer (23). A second distinct trajectory showed consistent directional flow suggesting that hillock cells may be acting as progenitors for basal cells (Figure 2B).…”

“…Regarding epithelial cells, we identified distinct subsets of hillock and club cells that have been described in normal prostate tissue (5,7,20). Club cells have been identified in human prostate tumors (23); however, we are the first to show and characterize the hillock cells in human prostate tumors ( Figure 2B ). Our RNA velocity analysis suggested a progenitor role for club cells which has been previously reported (23).…”

“…Club cells have been identified in human prostate tumors (23); however, we are the first to show and characterize the hillock cells in human prostate tumors ( Figure 2B ). Our RNA velocity analysis suggested a progenitor role for club cells which has been previously reported (23). We also saw a directional flow from hillock to basal cells, suggesting a second progenitor role of the hillock cells.…”

Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells

“…NO, as synthesized by eNOS and derived from endothelial cells, has been shown to promote the angiogenesis in tumor tissues [ 61 ]. However, one recent single-cell sequencing study shows that the proportion of endothelial cells in the prostate tumor tissues is quite low (less than 7% of total cell population), in 6 out of 7 localized prostate tumors obtained by radical prostatectomy [ 62 ], and thus their possible contribution in terms of eNOS-NO production to the growth of tumor cells or PCSCs is believed to be minimal. Moreover, emerging evidence demonstrates that PCSCs are resistant to androgen deprivation therapy and their expansion in cell population during the advanced progression would lead to CRPC which exhibits stem-like features [ 7 ].…”

High Keratin-7 Expression in Benign Peri-Tumoral Prostatic Glands Is Predictive of Bone Metastasis Onset and Prostate Cancer-Specific Mortality

“…KRT7 could act as a biomarker of a particular state, more than a marker of a distinct cellular population per se. The recent publication of a single-cell analysis of human primary prostate cancer uncovered heterogeneous cellular states in prostate epithelial cells from both cancer areas and paired-matched normal tissue adjacent to the tumor [ 59 ]. These results suggested a cellular plasticity, and either KRT17 or KRT7 were described as markers of particular cellular states (basal and club cells, respectively), thus providing some insight into a putative functional role of KRT7 [ 59 ].…”