New clues to what turns prostate cancers deadly

Only a fraction of prostate cancers become life threatening, but it’s impossible to predict which ones. In a surprising new study, researchers found that two signaling proteins used by nerve cells can become active in and around prostate tumors – and might play a role in driving the cancers to turn deadly.

The discovery could help point the way to understanding which prostate cancers are more likely to become dangerous, and help researchers find new ways to stop them.

The two proteins, in a class known as neuronal adhesion molecules, take part in conveying signals between nerve cells. “Based on our findings, we propose that the expression of neuronal adhesion molecules in prostate cancer cells mark tumors for a more aggressive, potentially metastatic phenotype,” said principal investigator Sebnem Ece Eksi, Ph.D., a post-doctoral scholar at CEDAR, the OHSU Knight Cancer Institute’s Cancer Early Detection Advanced Research Center. Nature Communications has published a paper describing the research.

Image: A prostate cancer cell (Anne Weston/Francis Crick Institute CC BY-NC 4.0)Understanding the advance of prostate cancer has proven difficult because the cells that make up a single tumor are strikingly diverse. Mutations and changes in gene activity give rise to sub-populations of tumor cells with new qualities, such as the ability to spread to other body parts. It’s been hard for researchers to grasp the diversity because samples don’t capture the full range of cells, and experiments have largely lumped cells together and measured the average of their behavior as a population.

In the new study, Eksi and colleagues were able to characterize the gene activity of more 14,000 single cells from prostate tumors surgically removed from 18 patients. They used a technique called single-cell combinatorial indexed sequencing. It’s a way to generate collections of DNA fragments that can be used to analyze genes for thousands of single cells at the same time. The technique was developed in the laboratory of Andrew Adey, Ph.D., an associate professor of molecular and medical genetics in the OHSU School of Medicine and senior author of the new study.

Experiments revealed that the neuronal adhesion molecule genes NRXN1 and NLGN1 are active in prostate cancer cells, in blood vessels in prostate cancer tissue, in immune cells infiltrating the prostate tumors, and in neuronal cells within prostate tumors.

Sebnem Ece Eksi, Ph.D.

“Our study allows us to formulate prominent questions about how synaptic molecules may regulate pathways in the epithelial and stromal cells of prostate tumors and how these interactions could possibly lead some prostate tumors to metastasize whereas other remain indolent,” Eksi said. “We think our findings will be of interest to molecular biologists working on other cancer types since the neuronal adhesion molecules uncovered in this study may be expressed in the neuronal and immune cell types innervating other cancers.”

The researchers also identified gene regulatory programs that define high-grade prostate tumors compared with low-grade prostate tumors. Low-grade tumors showed an enrichment of specific transcription factor binding sites, while high-grade tumors were enriched for a different set of transcription factor binding sites.

Further validating the finding, they identified the same regulatory signature in high grade tumors in a large public data set, The Cancer Genome Atlas. “Future research will determine whether disparate genomic changes observed in prostate cancer converge on common epigenomic profiles and if these present druggable targets in non-metastatic tumors,” the researchers wrote.

“Identification of gene regulatory programs shared by high and low-grade tumors present a strong opportunity to identify biomarkers for patient stratification despite the overwhelming molecular and cellular heterogeneity that exists in prostate cancer.”

Further reading:

Epigenetic loss of heterogeneity from low to high grade localized prostate tumours by Sebnem Ece Eksi, Alex Chitsazan, Zeynep Sayar, George V. Thomas, Andrew J. Fields, Ryan P. Kopp, Paul T. Spellman and Andrew C. Adey. Nature Communications (Dec. 15, 2021)

Innovation expands view into workings of single cells by Joe Rojas-Burke. Cancer Translated (July 6, 2021)

One response to “New clues to what turns prostate cancers deadly

  1. Very exciting marker for aggressive PCa. OHSU has become a real research and translational powerhouse.

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