NEW YORK – Researchers have uncovered a new prostate progenitor cell type that, under certain conditions, may contribute to the development of prostate cancer.
Researchers led by Dong Gao of the Chinese Academy of Science characterized more than 35,000 cells isolated from mouse prostates. The prostate epithelium includes luminal, basal, and neuroendocrine cells, but has not been well described.
Using a single-cell transcriptomic approach, the researchers uncovered three luminal cell types, including one they dubbed Luminal-C that they traced to two different locations in the prostate. As reported Monday in Nature Genetics, the newly identified Luminal-C cells are capable of self-renewal and could represent the cell of origin for prostate cancer. The researchers further confirmed the presence of Luminal-C cells in humans.
"These findings will enhance our understanding of normal prostate development and prostate cancer," Gao and his colleagues wrote in their paper.
The researchers profiled more than 8,500 cells from the prostates of four healthy adult male mice using droplet-based single-cell RNA-seq. The cells grouped into 11 different clusters that expressed different marker genes, many of which were known cluster markers. The luminal cells comprised three clusters, which they dubbed Luminal-A, Luminal-B, and Luminal-C. Luminal-C cells, for instance, were marked by the expression of Tacstd2, Ck4, and Psca.
Additionally, Luminal-A and Luminal-B cells were enriched for activity in protein folding, ion homeostasis, and body fluid secretion, while Luminal-C cells were involved in tissue development and epithelial cell differentiation. A cell trajectory analysis revealed a trajectory from Luminal-C to Luminal-A and Luminal-B.
By profiling an additional 13,744 cells from different parts of the prostate from 10-week-old mice, the researchers traced Luminal-A cells to the ventral prostate and Luminal-B cells in the anterior prostate and dorsal-lateral prostate. Luminal-C cells, though, were found throughout the prostate.
Based on co-immunofluorescence assays, they noted that some Luminal-C cells could be found distally and others proximally, and the researchers divided the group into two subgroups, Dist-Luminal-C and Prox-Luminal-C. Notably, Dist-Luminal-C cells were found at the distal prostate glandular invagination tips.
Both Dist-Luminal-C and Prox-Luminal-C cells are prostate luminal progenitor cells, and Dist-Luminal-C cells can regenerate the distal prostate luminal lineage, while Prox-Luminal-C cells can regenerate the proximal luminal lineage.
Both can also, the researchers found, initiate tumor development. Mice lacking the tumor suppressor gene Pten in the Luminal-C lineage developed prostate hyperplasia in the distal prostate invagination tips and proximal prostate. While the researchers noted that both Dist-Luminal-C and Prox-Luminal-C cells could serve as the cellular origins of prostate cancer, Dist-Luminal-C cells appear to be more efficient at doing so.
The researchers further isolated prostate cells from one male human donor and analyzed more than 11,000 prostate cells to find four clusters of luminal cells were present within humans. They uncovered human versions of the Luminal-A, Luminal-B, and Luminal-C cell clusters as well as an undefined luminal cell population.
Additionally, the researchers analyzed human prostate cancer biopsies to find the human versions of Luminal-C markers — TACSTD2, CK4, and PSCA — were more highly expressed in those samples than healthy prostate, suggesting Luminal-C cells could be the cells of origin for prostate cancer.
"Our study provides insights into the prostate lineage hierarchy, identifies Dist-Luminal-C cells as the luminal progenitor cell population in invagination tips, and suggests one of the potential cellular origins of prostate cancer," Gao and colleagues wrote.