How Dying Cells Reshape the Prostate

When patients are treated for prostate cancer with hormone therapy, one of the most common treatment strategies, the drug works partly by starving the prostate of testosterone, causing the gland to shrink. During this shrinkage, called regression, a large number of prostate cells die. But what happens to those dead cells, and how does the tissue respond? That’s the question that Rosalind and Morris Goodman Cancer Institute (GCI) researcher Luke McCaffrey and his team, led by Adda-Lee Graham-Paquin, PhD, sought to answer in the new Cell Death & Disease publication Apoptotic cell clearance triggers epithelial fate reprogramming during prostate regression.

The authors identified a new mechanism for dead cell clearance: the prostate’s own lining cells, known as epithelial cells, are the main “cleaners” responsible for engulfing and disposing of their dying neighbours, a process called efferocytosis. This was certainly surprising, because immune cells like macrophages are usually thought to carry out this job. Some macrophages were found to engulf dead cells, but epithelial cells were much more involved in the process.

The team found that this clean-up process not only tidies things up; it actively changes the identity of the surviving cells. When epithelial cells swallow dead neighbours, they undergo a metabolic shift, producing more lactate than usual. This lactate then modifies the DNA-packing proteins, called histones, effectively switching on genes that give the surviving cells a more progenitor state. This renewed progenitor population is responsible for regenerating the prostate tissue.

Importantly, genetically blocking the clean-up process in prostate epithelial cells in mice resulted in a less efficient shrinking of the prostate, and surviving cells failed to fully adopt this progenitor state.

Advancing our understanding of prostate cancer resistance

Hormone therapy in metastatic prostate cancer remains one of the widely used treatment strategies but can lead to resistance. Unfortunately, some patients develop castration resistant prostate cancer, an advanced, and often fatal, form of the disease.

“Understanding how the prostate rewires itself in response to hormone blockade helps us understand how the prostate responds to treatment, explains Adda-Lee, first author of the study. “This was the underlying reason behind the study: figure out what is happening to prevent this recurrence”.

This new study deepens our understanding of tissue remodelling and how prostate epithelial cells responds to hormone deprivation. It was led by GCI trainee Adda-Lee Graham-Paquin, PhD, along with GCI researchers Luke McCaffrey, PhD, and late Maxime Bouchard, PhD, as well as GCI associate member William Pastor, PhD. It was made possible with support from the Canadian Institutes of Health Research (CIHR) and the Charlotte and Leo Karassik Foundation.