Prostate cancer cells identified that may contribute to resistance to treatments.
Researchers characterized the dynamics of prostate cancer cells throughout the course of the disease.
Researchers characterized prostate cancer cell dynamics with single-cell resolution throughout the life span of the disease, from onset to the point at which the tumor no longer responds to hormone deprivation therapy. Their study in mice, published today in eLife, reveals an expansion of intermediary cells that correlates with treatment resistance and poor clinical outcomes in man. These cells are castration resistant, i.e. they continue to grow in the absence of testosterone, and could explain how prostate tumors become resistant to hormone treatments. The epithelium of the prostate gland – 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 that have altered their shape). However, an intermediate type of luminal cells more stem-like and castration-resistant has been previously proposed.
‘It has been hypothesized that normal luminal cells are capable of transforming into these progenitor cells under conditions of castration,’ explains lead author Alexandre Germanos, from the University of Washington (USA). “There is evidence that these cells contribute to the early development of prostate cancers and to treatment resistance in advanced cancers.”
To further the study, Germanos and colleagues used a mouse model of prostate cancer to create an “atlas of prostate cell composition and evolution” over the course of the disease. A gene called Pten , which encodes a tumor-suppressing enzyme, is inactive in most patients with advanced prostate cancer. The team used a technique called single cell RNA sequencingto compare epithelial and non-epithelial cell populations in healthy and Pten-deficient mice. Multiple epithelial cell types were observed in the prostate of healthy mice: basal, luminal, and luminal progenitor cells. In the prostate of Pten-deficient mice, they observed an expansion of intermediate luminal cells, likely derived from three cellular sources: basal cells, luminal progenitor cells, and differentiated luminal cells. This suggests that basal cells may transform into intermediate cells following Pten deletion.
The analysis also revealed that the prostates of Pten-deficient mice are highly enriched with immune cells that promote tumor production, creating a microenvironment that helps tumors evade suppression by the immune system. Pro – tumorigenic macrophages , a specialized cell type involved in the destruction of harmful organisms, are recruited by epithelial cells and by a cell type that contributes to the formation of connective tissue, fibroblasts. This suggests that disrupting the recruitment of tumor-associated macrophages could be a valid strategy to overcome resistance to immunotherapy in prostate cancer.
“Overall, our work highlights multiple epithelial and immune cell types that are crucial for prostate cancer initiation and progression, and sheds light on the interactions between specific cell populations that contribute to castration resistance,” concludes the author. Senior Andrew Hsieh.
“We wanted to provide a large, searchable resource for cancer researchers and encourage further research in this area. We then developed a publicly accessible, interactive website that allows scientists to perform cell- and gene-specific queries on all 50,780 cells analyzed in our study.”
- Defining cellular population dynamics at single-cell resolution during prostate cancer progression (elifesciences.org)