Scientists identify multiple cell types that may contribute to treatment resistance in prostate cancer – ScienceDaily

Researchers have characterized the dynamics of prostate cancer cells at a single cell resolution over the time span of the disease – from its onset to the point of androgen independence, where the tumor is no longer responsive to hormone deprivation therapy.

Their study in mice, published today in eLife, shows an expansion of interstitial cells that occurs in prostate cancer, which correlates with treatment resistance and poor clinical outcomes in humans. These cells are castration-resistant, meaning they continue to grow even without testosterone, and may explain how prostate tumors become resistant to hormone-related treatments.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in US men. This is due in large part to an incomplete knowledge of the cellular drivers behind disease progression and the risk of progression 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 made up of two types of epithelial cells: basal cells and highly differentiated luminal cells (cells that have changed shape). However, a more strain-like, castration-resistant intermediate of the luminal cells has previously been proposed.

“It has been suggested that normal luminal cells can proceed into these progenitor cells under castrated conditions,” says lead author Alexandre Germanos, PhD student in Molecular and Cellular Biology at the University of Washington, USA, and PhD student in the Department of Human Biology, Fred Hutchinson Cancer Center , UNITED STATES. “There is evidence that these cells contribute to the initial development of tumors in the prostate and resistance to treatment in advanced cancer, although this has yet to be confirmed in other CRPC models.”

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To study this further, Germanos and colleagues used a mouse model of CRPC to create an “atlas of prostate cellular composition and evolution” over the course of the disease.

A gene named pt, which encodes a tumor-suppressing enzyme, is inactive in the majority of patients with advanced prostate cancer. 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 that were absent pt.

In the prostates of healthy mice, they observed several epithelial cell types – basal, luminal and luminal progenitor cells. Absent from the prostate of mice ptthey observed an expansion of luminal interstitial cells that probably originate from three cellular sources – basal cells, luminal progenitor cells and differentiated luminal cells. This suggests that basal cells can transform into intermediate cells pt Deletion, which supports other findings in this area. The team also observed further expansion of cancerous intermediate cells after hormone withdrawal, which significantly increased cell diversity within a tumor (known as tumor heterogeneity). They showed that this heterogeneity can be restricted by inhibiting protein synthesis.

The team then attempted to characterize the effects of this hormone-deprivation-induced intermediate cell expansion. In the interstitial cells, they discovered that a 5-gene signature is specifically enriched. Using two sets of mass RNA sequencing data from prostate cancer patients, they showed that the signature is associated with treatment resistance and poor clinical outcomes. In addition, the signature is enriched in a subset of metastatic human prostate cancer cells — tumors that can spread — but not in the primary tumor cells.

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These results suggest that a 5-gene signature derived from mouse models of prostate cancer could be important in understanding human disease. The presence of this gene signature can serve as a useful prognostic tool to predict treatment resistance and outcomes in patients. The authors call for further studies to validate the role of this signature and intermediate cell populations in individuals with prostate cancer.

Their analysis also revealed that the prostates in mice without pt is highly enriched with immune cells that promote tumor formation, creating a microenvironment that helps tumors evade suppression by the immune system. Protumorigenic macrophages, a specialized cell type involved in the destruction of harmful organisms, are recruited from epithelial cells and a cell type that helps form connective tissue called fibroblasts. This suggests that disrupting tumor-associated macrophage recruitment could be a valid strategy to overcome immunotherapy resistance in prostate cancer.

“Taken together, our work highlights multiple epithelial and immune cell types critical to prostate cancer development and progression, and sheds light on the interactions between specific cell populations that contribute to castration resistance,” concludes senior author Andrew Hsieh, associate professor at the Department of Human Biology, Fred Hutchinson Cancer Center, and Department of Medicine and Genomics (affiliate), University of Washington.

“We wanted to provide a broad, searchable resource for cancer researchers and encourage further research in this area. That’s why we developed a publicly accessible and interactive website that allows scientists to perform cell- and gene-specific queries on all 50,780 cells analyzed in our study.”

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Materials provided by eLife. Note: Content can be edited for style and length.

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