Prostate cancer cell dynamics at a single-cell resolution across the timespan of the disease — from its beginning to the point of androgen independence, where the tumour no longer responds to hormone, deprivation therapy has now been characterised.
The study in mice, published in eLife, reveals an expansion of intermediate cells that occurs in prostate cancer, which correlates with resistance to treatment and poor clinical outcomes in humans. These cells are castration-resistant, meaning they continue to grow in the absence of testosterone and could explain how prostate tumours become resistant to hormone-related treatments.
Prostate cancer is the most diagnosed form of cancer, and the second-leading cause of cancer-related deaths in males in the U.S. This is due to an incomplete knowledge of the cellular drivers behind the disease’s progression and the risk of progressing to castration resistant prostate cancer (CRPC).
The prostate gland epithelium — a type of body tissue that forms the surface of glands and organs — is typically composed of two types of epithelial cells: basal cells and highly differentiated luminal cells (cells which have altered in form). However, a more stem-like, castration-resistant intermediate of the luminal cells has previously been proposed.
“It has been suggested that normal luminal cells are able to transition into these progenitor cells under castrate conditions,” lead author Alexandre Germanos at the University of Washington, U.S., says in a release. “There is evidence that these cells contribute to the initial development of tumours in the prostate and resistance to treatment in advanced cancers, although this is yet to be confirmed in other models of CRPC.”
To study this further, the authors used a mouse model of the CRPC to create an ‘atlas of prostate cellular composition and evolution’ through the course of the disease.
A gene called Pten, which codes for a tumour-suppressing enzyme, is inactive in majority of advanced prostate cancer patients. The team used a technique called single-cell RNA sequencing to compare the epithelial and non-epithelial cell-type populations in healthy mice and those lacking Pten.
In the prostate of healthy mice, they observed multiple epithelial cell types — basal, luminal and luminal progenitor cells. In the prostate of mice lacking Pten, they observed an expansion of luminal intermediate cells, likely derived from three cellular sources — basal cells, luminal progenitor cells and differentiated luminal cells. This suggests that basal cells can transform into intermediate cells upon Pten deletion, supporting other findings in the field. The team also observed further expansion of cancerous intermediate cells upon hormone deprivation which significantly increased the diversity of cells within a tumour (known as tumour heterogeneity), says the release.
In the intermediate cells, the researchers discovered that a 5-gene signature is specifically enriched. Using two datasets of bulk RNA-sequencing from prostate cancer patients, they showed that the signature is associated with treatment resistance and poor clinical outcomes. Furthermore, the signature is enriched in a subset of metastatic human prostate cancer cells — tumours that are able to spread — but not in the primary tumour cells.
These findings suggest that a 5-gene signature derived from mouse models of prostate cancer may have importance in understanding human disease. The presence of this gene signature may serve as a useful prognostic tool for predicting treatment resistance and outcomes in patients.