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

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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: 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
• Journal: The Journal of pathology (J Pathol) Vol. 243 Issue 1 Pg. 51-64 (09 2017) ISSN: 1096-9896 [Electronic] England
• PMID: 28603917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• AR protein, mouse
• Androgen Antagonists
• Antineoplastic Agents, Hormonal
• Ataxin-1
• Atxn1 protein, mouse
• Biomarkers, Tumor
• Integrin alpha6
• Keratin-4
• Receptors, Androgen
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Androgen Antagonists (pharmacology)
• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Ataxin-1 (metabolism)
• Biomarkers, Tumor (deficiency, genetics)
• Cell Lineage
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Integrin alpha6 (metabolism)
• Keratin-4 (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Recurrence, Local
• Neoplastic Stem Cells (drug effects, enzymology, pathology, transplantation)
• Oligonucleotide Array Sequence Analysis
• PTEN Phosphohydrolase (deficiency, genetics)
• Phenotype
• Prostatic Neoplasms, Castration-Resistant (drug therapy, enzymology, genetics, pathology)
• Receptors, Androgen (drug effects, metabolism)
• Signal Transduction