RUNX1 marks a luminal castration-resistant lineage established at the onset of prostate development.

Renaud Mevel,Susan Mason,Hing Y Leung,Karen Blyth,Rahima Patel,Georges Lacaud,Imran Ahmad,Ivana Steiner,Pedro Oliveira,Laura Ca Galbraith,Muhammad Zh Fadlullah,Esther Baena

doi:10.7554/elife.60225

Abstract

The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.

Highlights

The prostate is a glandular organ of the mammalian male reproductive system
These initial buds grow into the surrounding mesenchyme to develop postnatally and through puberty into a branched ductal network organized in distinct pairs of lobes, known as the anterior prostate (AP), dorsolateral prostate (DLP), and ventral prostate (VP) (Sugimura et al, 1986a)
Using mouse models, combined with lobe-specific single-cell transcriptomic profiling of adult, castrated, and developing prostates, we show that RUNX1+proximal luminal cells represent a distinct lineage established at the onset of prostate development, displaying intrinsic castration-resistant and self-sustaining properties

Summary

Introduction

Prostate development starts during embryogenesis at embryonic day (E) 15.5–16.5 with the emergence of the first prostatic buds from the rostral end of the urogenital sinus (UGS) (Bhatia-Gaur et al, 1999; Georgas et al, 2015; Keil et al, 2012; Toivanen and Shen, 2017). These initial buds grow into the surrounding mesenchyme to develop postnatally and through puberty into a branched ductal network organized in distinct pairs of lobes, known as the anterior prostate (AP), dorsolateral prostate (DLP), and ventral prostate (VP) (Sugimura et al, 1986a).

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Conclusion