Mystery Cell Found: Why Enlarged Prostate Strikes Only One Zone of the Gland

For decades, doctors have known a curious anatomical fact about the aging male body: when the prostate enlarges, it almost always does so in one specific neighborhood of the gland, leaving the rest of the tissue largely untouched. Now researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center believe they have found a cellular suspect that may explain this striking regional bias. By mapping gene activity across nearly 130,000 individual prostate cells, the team identified a previously unrecognized subtype of basal epithelial cell that is concentrated precisely in the zone where benign prostatic hyperplasia, or BPH, develops — and is markedly expanded in tissue from men who have the condition. The discovery, published in The Journal of Pathology, offers one of the most detailed cellular explanations yet for why this extraordinarily common condition chooses its location so selectively.

BPH is not cancer, but it is hardly a minor inconvenience. The noncancerous overgrowth of prostate cells becomes increasingly common as men age, and as the gland swells it can compress the urethra, the narrow tube that carries urine out of the body. The consequences are familiar to millions of older men: frequent urination, repeated nighttime trips to the bathroom, a weak urinary stream, and the frustrating sensation that the bladder never fully empties. Despite how widespread the condition is, the biological events that set it in motion — and in particular the question of why it arises almost exclusively in one region of the prostate — have remained stubbornly unresolved. Senior author Vasan Yegnasubramanian, a professor of oncology, pathology, and radiation oncology and molecular radiation sciences at the Johns Hopkins Kimmel Cancer Center and director of inHealth Precision Medicine at Johns Hopkins Medicine, noted that although BPH affects millions of men worldwide, scientists still do not fully understand why it develops primarily in the transition zone while other regions of the gland remain relatively unaffected.

That regional puzzle is rooted in the prostate’s internal architecture. The gland is not a uniform organ but is divided into several anatomically and biologically distinct compartments, most notably the peripheral zone, the central zone, and the transition zone. These regions differ in their cellular makeup and in their vulnerability to disease, and the split is dramatic: BPH arises almost exclusively in the transition zone, the area surrounding the urethra, while the majority of prostate cancers emerge in the peripheral zone. Understanding why the same organ hosts two such different disease patterns has long been a goal of prostate biology, and it suggests that the answer lies in fundamental differences in the cells that populate each zone.

To pursue that question at single-cell resolution, the research team, led by Yegnasubramanian together with Rulin Wang, a research associate and the study’s first author, and Angelo De Marzo, professor of pathology at the Johns Hopkins University School of Medicine and associate director of cancer research pathology at the Kimmel Cancer Center, turned to single-cell RNA sequencing. This technology allows investigators to determine which genes are switched on or off in individual cells, rather than averaging signals across a bulk sample in which rare cell types can vanish into the noise. The team studied noncancerous prostate tissue collected from 10 men undergoing surgery for localized prostate cancer, obtaining samples from all three major zones of the gland and profiling gene expression in nearly 130,000 individual cells.

The first task was cartographic: identifying the major cell types present throughout the prostate and confirming how they were distributed across zones. With that atlas in hand, the researchers zoomed in on basal epithelial cells, a population that helps form the lining of the prostate and is thought to include progenitor-like cells capable of contributing to tissue maintenance and repair. Rather than finding a single homogeneous basal population, the analysis revealed that these cells split into four distinct molecular subtypes — a level of diversity that conventional histology had not exposed.

One of those four subtypes immediately stood out. Its cells expressed high levels of a gene called WIF1, along with several other genes, and their distribution across the gland was anything but random. Additional laboratory tests confirmed that these WIF1-positive basal cells were abundant in the transition zone but nearly absent from the peripheral and central zones. In other words, the researchers had found a cell population whose geographic footprint within the prostate matched, almost exactly, the territory where BPH takes hold.

The molecular profile of these cells offered further clues about what they might be doing. According to Wang, the analysis revealed that the cells possess molecular features associated with tissue remodeling that could contribute to prostate enlargement, as well as an ability to communicate with neighboring cells, suggesting they may help establish the unique biological environment of the transition zone. Tissue remodeling — the orchestrated breakdown and rebuilding of structural components — is a normal part of organ maintenance, but when it runs unchecked it can drive the kind of nodular overgrowth seen in BPH. A cell type equipped with remodeling programs and embedded in the exact region where that overgrowth occurs is a compelling candidate for a local driver of the disease process.

Perhaps most tellingly, the team found that WIF1-positive basal cells are expanded in BPH tissues. That expansion raises the possibility, the researchers say, that these cells contribute to the regional processes that make the transition zone particularly susceptible to BPH. The gene whose name the cells carry, WIF1, encodes a Wnt inhibitory factor, a secreted molecule that modulates Wnt signaling — a pathway with well-established roles in development, stem cell behavior, and tissue growth. The presence of a Wnt-pathway regulator in a remodeling-competent basal population enriched at the BPH epicenter suggests a plausible mechanism by which local signaling environments could shape where and how the gland enlarges, though the study’s authors frame this as a foundation for future work rather than a settled causal story.

The significance of the finding lies less in any single gene than in the strategy it validates. Bulk analyses of prostate tissue have long averaged together the signals of many cell types, obscuring the rare, regionally restricted populations that may hold the key to zonal disease patterns. By dissecting the gland zone by zone at single-cell resolution, the Hopkins team showed that the transition zone carries its own distinctive cellular identity, embodied in a basal cell subtype found almost nowhere else in the organ. That identity, the researchers suggest, may be what renders the transition zone uniquely prone to the proliferative and remodeling processes of BPH — and, by extension, may help explain why the peripheral zone instead becomes the favored soil for prostate cancer.

By uncovering this distinct cell population associated with the region where BPH begins, the research provides new insight into the cellular mechanisms underlying prostate growth and remodeling, and it offers a foundation for future studies aimed at understanding how the condition develops. The long-term hope, the researchers say, is that a clearer picture of the transition zone’s biology will ultimately support more precise ways to prevent, diagnose, and treat BPH — potentially allowing therapies that target the specific cell programs driving enlargement rather than broadly suppressing prostate growth. The study also involved contributions from Qizhi Zheng, Mindy Graham, Ajay Vaghasia, Jianyong Liu, Jordan Gregg, Tracy Jones, Anuj Gupta, Nicole Castagna, Yan Zhang, Kornel Schuebel, Jennifer Meyers, Alyza Skaist, Dixie Hoyle, Jasmine Kung, Jessica Hicks, Alok Mishra, Yuhan Yang, and William Nelson. The work was supported by the National Institutes of Health and the National Cancer Institute, the Prostate Cancer Foundation, and several philanthropic and institutional funds, including the Patrick G. Walsh Fund and the Maryland Cigarette Restitution Fund.

Subject of Research: Identification of a WIF1-positive basal epithelial cell type in the prostate transition zone associated with benign prostatic hyperplasia

Article Title: Newly identified prostate cell type may help explain why enlarged prostate develops in one region of gland

Article References: Newly identified prostate cell type may help explain why enlarged prostate develops in one region of gland. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: benign prostatic hyperplasia, prostate, transition zone, basal epithelial cells, WIF1, single-cell RNA sequencing, Johns Hopkins, tissue remodeling, prostate zones, urology, aging, cell biology