Stem and progenitor cells of the adult prostate epithelium have historically been believed to reside mainly or exclusively within the basal cell compartment and to possess basal-like phenotypic characteristics. Within the past decade, evidence of the existence of luminal epithelial cells exhibiting stem/progenitor properties has been obtained by lineage tracing and by functional characterization of sorted luminal-like cells. In 2020, the boom of single-cell transcriptomics led to increasingly exhaustive profiling of putative mouse luminal progenitor cells and, importantly, to the identification of cognate cells in the human prostate. The enrichment of luminal progenitor cells in genetically modified mouse models of prostate inflammation, benign prostate hypertrophy and prostate cancer, and the intrinsic castration tolerance of these cells, suggest their potential role in prostate pathogenesis and in resistance to androgen deprivation therapy. This Review bridges different approaches that have been used in the field to characterize luminal progenitor cells, including the unification of multiple identifiers employed to define these cells (names and markers). It also provides an overview of the intrinsic functional properties of luminal progenitor cells, and addresses their relevance in mouse and human prostate pathophysiology.
Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.
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