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

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 LSC^med according to their FACS profile (Lin⁻/Sca-1⁺/CD49f^med). Here we investigated the prevalence and castration-resistance of LSC^med in various mouse models of prostate tumorigenesis (Pb-PRL, Pten^pc−/−, Hi-Myc mice). LSC^med prevalence is low (~8%, similar to WT) in Hi-Myc mice where prostatic androgen receptor signaling is unaltered, but is significantly higher in two other models where androgen receptor signaling is decreased, rising up to >80% in Pten^pc−/− prostates. LSC^med tolerate androgen deprivation and persist or are enriched 2–3 weeks after castration. The tumor-initiating properties of LSC^med from Pten^pc−/− mice were demonstrated by regeneration of tumors in vivo. Transcriptomic analysis revealed LSC^med 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 signaling is markedly decreased, explaining why LSC^med tolerate androgen-deprivation. This also illuminates why Pten^pc−/− tumors are castration-resistant since LSC^med represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC^med on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC^med in various mouse prostate specimens. In castrated Pten^pc−/− prostates, there was significant proliferation of CK4⁺ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSC^med 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.

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