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

Elife. 2020 Oct 7;9:e60225. 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.

Keywords: RUNX1; development; developmental biology; intrinsic castration-resistance; mouse; prostate; proximal luminal cells; regenerative medicine; single-cell RNA-seq; stem cells.

Plain Language Summary

The prostate is part of the reproductive organs in male mammals. Many of the cells lining the inside of the prostate – known as ‘luminal cells’ – need hormones to survive. Certain treatments for prostate cancer, including surgical and chemical castration, lead to fewer hormones reaching the prostate, which shrinks as luminal cells die. But some of these luminal cells are able to survive the damaging effects of castration, rebuilding the prostate upon treatment with hormones, which can lead to the cancer reappearing. It is unclear which type of luminal cells survive during periods without hormones and are responsible for regenerating the prostate. RUNX1 is a protein responsible for switching genes on and off, and is usually found in blood cells, which it helps to mature and perform their roles, but has also been detected in tissues that depend on hormones. Since the luminal cells of the prostate rely on hormones, could RUNX1 also be present in these cells? To answer this question, Mével et al. used mice to determine where and when RUNX1 is found in prostate cells. Mével et al. detected high levels of RUNX1 in a patch of luminal cells at the base of the prostate. Samples of these cells were taken for further testing from developing mouse embryos, healthy adult mice and mice in which the prostate was regenerating after surgical castration. Mével et al. found that these cells were a distinct subtype of luminal cells that were able to resist the effects of castration – they survived without hormones. Though these cells were present during the early stages of prostate embryonic development and in healthy adult prostate tissue, they were not responsible for rebuilding the prostate after castration. Mével et al.’s results indicate that, in mice, RUNX1 may act as a marker for a subset of luminal cells that can survive after castration. Further probing the roles of these castration-resistant luminal cells in normal and cancerous prostate tissue may improve the outcome of patients with prostate cancer treated with hormone deprivation therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Core Binding Factor Alpha 2 Subunit / physiology*
  • Epithelium / metabolism
  • Male
  • Mice
  • Orchiectomy
  • Prostate / cytology
  • Prostate / growth & development*
  • Prostate / metabolism

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Runx1 protein, mouse

Associated data

  • GEO/GSE151944