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

Abstract

22The development of castration-resistant prostate cancer is a major complication of androgen-23 deprivation therapy. However, the origin and identity of these resistant cells remains controversial. 24Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal 25 cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct 26 from the previously identified NKX3.1 + luminal castration resistant cells. Using scRNA-seq profiling and 27 genetic lineage tracing, we show that RUNX1 + PLCs are unaffected by androgen deprivation, and do not 28 contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a 29 transcriptionally similar RUNX1 + population emerges at the onset of embryonic prostate specification to 30 populate the proximal region of the ducts. Collectively, our results reveal that RUNX1 + PLCs is an intrinsic 31 castration-resistant and self-sustained lineage that emerges early during prostate development and 32 provide new insights into the lineage relationships of the prostate epithelium.

Role of Runx2 in prostate development and stem cell function

“…Consistent with these findings, query of a recently published single cell RNA sequencing (scRNAseq) data base from adult mouse prostate (https://shiny.cruk.manchester.ac.uk/pscapp/) detected Runx2 expression predominately in a luminal cell cluster enriched in other markers, such as Krtr8 , Krt4 , Epcam , Psca , and Wfdc2 (Lum‐D) and, to a lesser extent, in a basal cell cluster enriched in Krt5 and Krt14 . However, it was low in other luminal clusters expressing Sbp and Spink1 (Lum‐A) or Tmg4 , Nkx3.1 , and Pbsn (Lum‐B) 46 . This suggests that Runx2 is expressed in discrete luminal and basal cell populations that may function at specific stages of prostate development.…”

Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

“…Enhanced Tgf-β signalling has been linked with the presence of quiescent epithelial progenitors in the proximal/periurethral region of the mouse prostate 25,26 . Recent single-cell studies have confirmed the enrichment of a variety of epithelial progenitors -basal, luminal proximal (LumP), and periurethral (PrU) cells -in this anatomical district, though also present at low frequency in the distal compartment [27][28][29][30][31][32] . Such cells are known to be particularly quiescent during homeostasis 33,34 , but also to exhibit extensive regenerative potential in ex-vivo assays 31,35 .…”

“…Initially, we set out to assess whether mouse prostate organoids are a representative and informative model for the study of the prostate epithelium, in light of recent discoveries on prostate cellular heterogeneity and dynamics 27,28,[30][31][32]34,38 . Considering our interest in signalling, we focused on a culture method in defined media conditions.…”