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

  1. Renaud Mevel
  2. Ivana Steiner
  3. Susan Mason
  4. Laura CA Galbraith
  5. Rahima Patel
  6. Muhammad ZH Fadlullah
  7. Imran Ahmad
  8. Hing Y Leung
  9. Pedro Oliveira
  10. Karen Blyth
  11. Esther Baena
  12. Georges Lacaud  Is a corresponding author
  1. Cancer Research UK Manchester Institute, The University of Manchester, United Kingdom
  2. Cancer Research UK Beatson Institute, United Kingdom
  3. The Christie NHS Foundation Trust, United Kingdom

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.

Data availability

Raw sequencing files and processed gene expression matrices have been deposited in the NCBI Gene Expression Omnibus under the accession number GSE151944. The processed datasets for both mouse adult prostate and UGS prostate explant cultures can be accessed via a searchable R Shiny application available at http://shiny.cruk.manchester.ac.uk/pscapp/. All code used to process data and generate figures is available on a public GitHub repository at https://github.com/glacaud/prostate-scRNAseq.

The following data sets were generated

Article and author information

Author details

  1. Renaud Mevel

    Stem Cell Biology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Ivana Steiner

    Prostate Oncobiology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2744-1952
  3. Susan Mason

    Transgenic models of cancer, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Laura CA Galbraith

    Transgenic models of cancer, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Rahima Patel

    Stem Cell Biology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Muhammad ZH Fadlullah

    Stem Cell Biology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Imran Ahmad

    Models of advanced prostate cancer, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Hing Y Leung

    Urology Research Group, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Pedro Oliveira

    Department of Pathology, The Christie NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Karen Blyth

    Urology Research Group, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Esther Baena

    Prostate Oncobiology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Georges Lacaud

    Stem Cell Biology, Cancer Research UK Manchester Institute, The University of Manchester, Macclesfield, United Kingdom
    For correspondence
    georges.lacaud@cruk.manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5630-2417

Funding

Cancer Research UK (C5759/A20971)

  • Esther Baena
  • Georges Lacaud

Cancer Research UK (C596/A17196)

  • Karen Blyth

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were approved by the Animal Welfare and Ethics Review Body (AWERB) of the Cancer Research UK Manchester Institute and conducted according to the UK Home Office Project Licence (PPL 70/8580). Genetic lineage-tracing experiments were performed at the Beatson Biological Services Unit (PPL 70/8645 & P5EE22AEE) and approved by the University of Glasgow AWERB. Mice were maintained in purpose-built facility in a 12-hour light/dark cycle with continual access to food and water. All animal procedures were performed on adult males at least 7 weeks of age. Surgical castration was carried out under aseptic conditions.

Reviewing Editor

  1. Wilbert Zwart, Netherlands Cancer Institute, Netherlands

Version history

  1. Received: June 20, 2020
  2. Accepted: October 6, 2020
  3. Accepted Manuscript published: October 7, 2020 (version 1)
  4. Version of Record published: November 5, 2020 (version 2)

Copyright

© 2020, Mevel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Renaud Mevel
  2. Ivana Steiner
  3. Susan Mason
  4. Laura CA Galbraith
  5. Rahima Patel
  6. Muhammad ZH Fadlullah
  7. Imran Ahmad
  8. Hing Y Leung
  9. Pedro Oliveira
  10. Karen Blyth
  11. Esther Baena
  12. Georges Lacaud
(2020)
RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development
eLife 9:e60225.
https://doi.org/10.7554/eLife.60225

Share this article

https://doi.org/10.7554/eLife.60225

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