Unravelling the Luminal Progenitor-Inflammation-STAT5 Vicious Circle in Benign Prostate Hyperplasia – PROSTAT5

Benign prostate hyperplasia (BPH) is the most prevalent disease in the ageing male. This common urological condition is caused by the progressive, non-malignant enlargement of the prostate gland. BPH leads to lower urinary tract symptoms (LUTS) that can start to be observed around the age of 50. There are currently 2 million symptomatic cases in France and their number will rise with increased life expectancy. LUTS markedly affect the quality of life of patients and are associated with high personal and societal costs. Symptomatic treatments aimed to relief LUTS by reducing smooth muscle tone do not prevent disease progression, therefore their efficacy is often transient. Etiologic treatments targeting androgen signaling (named 5ARI) are initially efficient, but exhaustion of beneficial effects is observed within a few years. In addition, these treatments generate sexual side effects (loss of libido, erectile dysfunction) leading to low compliance. The ultimate therapeutic option for BPH patients is surgery. In addition to common risks linked to any surgery, this strategy almost systematically induces irreversible sexual side effects (retrograde ejaculation). In all, a better therapeutic management of these patients is necessary. However, the BPH pathophysiology remains poorly understood.

Partner 1 holds a mouse model of BPH, called Pb-PRL, resulting from prostate-specific expression of prolactin. This model recapitulates many cellular and functional features of the human disease including tissue hypertrophy, epithelial and stromal hyperplasia, intraprostatic inflammation and LUTS-like disorders. This model led to the discovery by partner 1 of a particular set of prostatic cells called "luminal progenitors". The latter are rare in the healthy prostate, but markedly amplified in the hyperplastic prostate of Pb-PRL mice. In addition, they are resistant to 5ARI therapy. Our working hypothesis is that luminal progenitors participate in BPH development and progression. In the human prostate, these cells (named 'Club cells') are found mainly in the transition zone, where BPH develops. As in mice, Club cells are amplified in BPH and may therefore directly contribute to BPH-associated obstructive LUTS by compressing the urethra. Chronic prostatic inflammation has been associated to LUTS severity. Strikingly, the amplification of luminal progenitor/Club cells parallels intraprostatic inflammation in both mice and men, suggesting functional interactions between these two cell compartments.

In Pb-PRL mice, prolactin leads to constitutive STAT5 signaling in various cell types which ultimately results in increased prevalence of luminal progenitor cells and peri-glandular inflammation. Luminal progenitors express various pro-inflammatory cytokines suggested to promote BPH progression. Immune cells are also well-known cytokine-secreting cells, so they likely contribute to the perpetuation of STAT5 signaling, as well as possibly other deleterious pathways at the interface of inflammation and epithelial hyperplasia. Collectively, these data suggest a model in which, in BPH, epithelial hyperplasia involves abnormal luminal progenitor cell expansion and development of a pro-inflammatory microenvironment, driven by a vicious circle implicating STAT5 signaling under the paracrine control of inflammatory cells and of progenitor cells themselves as perpetuators of the disease.

This project aims to map the cartography of this multicellular network focusing on the interaction between luminal progenitors and infiltrating immune cells as well as on the role of chronic STAT5 signaling. Our interdisciplinary consortium involves experts in prostate biology (partner 1), immunology (partner 2) and human prostate pathology and urology (partners 3 & 4). The study will be conducted using relevant mouse models, prospective human BPH biocollections and single-cell OMICs technologies, and will challenge new therapeutic options in preclinical BPH model