A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours

Lucila Sackmann Sala, Florence Boutillon, Giulia Menara, Andréa De Goyon-Pélard, Mylène Leprévost, Julie Codzamanian, Natalie Lister, Jan Pencik, Ashlee Clark, Nicolas Cagnard, Christine Bole-Feysot, Richard Moriggl, Gail P. Risbridger, Renea A. Taylor, Lukas Kenner, Jacques Emmanuel Guidotti, Vincent Goffin

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9 Citations (Scopus)

Abstract

Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/-, and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

Original languageEnglish
Pages (from-to)51-64
Number of pages14
JournalJournal of Pathology
Volume243
Issue number1
DOIs
Publication statusPublished - Sep 2017

Keywords

  • Androgen signalling
  • Castration resistance
  • CK4
  • Epithelial cells
  • Progenitor cell
  • Prostate cancer

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