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Prostate Cells With Regenerative Capability Uncovered by Single-Cell Transcriptomics

NEW YORK – A team led by investigators at Memorial Sloan Kettering Cancer Center, the Broad Institute, and Massachusetts Institute of Technology has tracked down differentiated prostate cell populations that appear capable of reprogramming and regeneration in mouse and human prostate tissues exposed to treatments for advanced prostate cancer.

"Because cancer cells often exploit the stem-like niches used by normal cells, these insights could suggest new prostate cancer therapies that might be useful in combination with [androgen receptor] blockade," co-senior and co-corresponding authors Charles Sawyers of Memorial Sloan Kettering and Aviv Regev of the Broad Institute, along with their colleagues, wrote in a study published in Science on Thursday.

Starting with droplet-based single-cell RNA sequencing on close to 13,400 individual mouse prostate cells, the researchers uncovered nearly two dozen epithelial and non-epithelial cell clusters, including clusters of luminal cells with apparent ties to prostate regeneration in subsequent mouse prostate tissue regeneration experiments.

Comparable populations appeared in organoids developed from luminal cells taken from human prostate tissues after pharmacologic castration, they reported, and hinted at an unappreciated role for some differentiated cells in regenerating prostate tissue after androgen deprivation treatments.

"Our study has uncovered a previously unknown complexity of cell subtypes within the prostate," the authors reported. "In addition, we found that after castration, most persisting luminal cells (rather than a rare population of stem cells) contribute to the proliferative response, akin to the regenerative process observed after liver injury."

The combination of surgery and pharmacological castration used to treat advanced prostate cancer cases is known to prompt luminal epithelial cell loss and significant prostate shrinkage, the team explained. But past studies have shown that mouse models can replace such lost tissue after exposure to testosterone, raising questions about the cell types involved in this tissue regeneration.

To explore that process in more detail, the researchers sequenced the transcriptome in 13,398 individual mouse prostate cells, uncovering gene expression clusters corresponding to 16 non-epithelial cell populations and half a dozen populations of epithelial cells that were characterized in more detail with the help of marker gene expression.

When the team followed the process of chemical castration and prostate regeneration in mice using single-cell RNA-seq and lineage-tracing experiments, meanwhile, it saw expansions of certain existing prostate cell populations, including differentiated luminal cells and rarer luminal cells with some stem-like expression features.

Together with results from human prostate samples assessed using organoid models, imaging, single-cell RNA-seq, and other approaches, the findings suggest that chemical castration may reprogram some prostate cell subpopulations to make them more similar to stem cells.

"A precise molecular understanding of how differentiated normal luminal cells acquire stem-like regenerative properties could provide insight into ways to interfere with this process in malignant prostate cells," the authors wrote, noting that this process may involve contributors from the microenvironment.