5‐Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia

Joseph, Diya B.; Henry, Gervaise H.; Malewska, Alicia; Reese, Jeffrey; Mauck, Ryan; Gahan, Jeffrey; Hutchinson, Ryan; Mohler, James L.; Roehrborn, Claus G.; Strand, Douglas W.

doi:10.1002/path.5857

Cited by 35 publications

(38 citation statements)

References 38 publications

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“…Similar findings were recently reported in human benign prostate hyperplasia (BPH). Treatment with 5α reductase inhibitors, which are used to reduce intraprostatic androgen receptor signaling in BPH cells, was associated with a shift of luminal cells towards a Club-like identity [ 64 ]. In keeping with this, we and others have demonstrated that mouse LSC med -like luminal progenitor cells are intrinsically castration tolerant in both healthy and cancer contexts [ 5 , 9 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Baurès

Lombardi

Martino

et al. 2022

Cancers

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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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Section: Discussionmentioning

confidence: 99%

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Baurès

Lombardi

Martino

et al. 2022

Cancers

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“…6,7 However, we recently showed that the response to 5ARI treatment is highly variable. 8 Given the pleomorphic nature of BPH and the targeted killing of luminal epithelia by 5ARIs, we hypothesized that a higher stromal content may predict 5ARI failure. 4 Biopsies are not routinely performed for evaluating BPH histology, which means that noninvasive tests are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Current AUA guidelines recommend 5ARI treatment for patients with symptomatic BPH that display prostate volume ≥30 cc and PSA ≥1.5 ng/ml 6,7 . However, we recently showed that the response to 5ARI treatment is highly variable 8 . Given the pleomorphic nature of BPH and the targeted killing of luminal epithelia by 5ARIs, we hypothesized that a higher stromal content may predict 5ARI failure 4 .…”

Section: Discussionmentioning

confidence: 99%

PSA density is associated with BPH cellular composition

et al. 2022

Self Cite

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Background: Current AUA guidelines recommend 5 alpha reductase inhibitor (5ARI) treatment for patients with obstructive benign prostatic hyperplasia (BPH) that display prostate volume ≥30 cc and total prostate specific antigen (PSA) ≥1.5 ng/ml. However, BPH is highly pleomorphic and response to 5ARIs is highly variable. An understanding of cellular composition based on a noninvasive PSA density test could lead to improved clinical decision making. Methods:The histological composition of 307 BPH specimens was scored by a pathologist for stromo-glandular content and associated with total PSA, prostate volume, PSA density and other clinical variables using univariate and multivariate linear regression. Results:The percentage of glandular composition in prostates of 5ARI-naïve men was positively and independently associated with PSA and PSA density. It was determined through statistical modeling that a PSA density ≤0.05 ng/ml 2 associated with a glandular composition of ≤30% with 76% sensitivity.Conclusions: PSA density could provide a decisive variable for estimating BPH cellular content and may eventually improve selection of patients for 5ARI treatment. Further work is needed to demonstrate that patients with higher glandular content are more responsive to 5ARI treatment.

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“…The development of a whole transcriptome panel for both human and mouse enables a wide range of translational, clinical, and basic biology research. For example, researchers have used WTA to identify focal changes in gene expression in kidney allograft rejection (Salem et al 2022), determine cell types affected by SARS-CoV-2 infection in the olfactory epithelium (Khan et al 2021), characterize functional gene expression differences across a heterogenous central nervous system tumor (Dottermusch et al 2021), and assess structure-specific responses to treatment in prostate hyperplasia (Joseph et al 2022). To promote these broad research applications, we have shown that WTA is compatible with a variety of tissue types and sample preservation methods (FFPE, fresh frozen, and fixed frozen).…”

Section: Discussionmentioning

confidence: 99%

Spatially resolved whole transcriptome profiling in human and mouse tissue using Digital Spatial Profiling

Sm¹,

Fropf²,

Br³

et al. 2021

Preprint

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Emerging spatial profiling technology has enabled high-plex molecular profiling in biological tissues, preserving the spatial and morphological context of gene or protein expression. Here we describe expanded chemistry for the Digital Spatial Profiling platform to quantify whole transcriptomes in human and mouse tissues using a wide range of spatial profiling strategies and sample types. We designed multiplexed in situ hybridization probe pools targeting the protein-coding genes in the human and mouse transcriptomes, hereafter referred to as the human or mouse Whole Transcriptome Atlas (WTA). We validated the human and mouse WTA assays using cell lines to demonstrate concordance with orthogonal gene expression profiling methods in profiled region sizes ranging from ~10-500 cells. By benchmarking against bulk RNAseq and single-molecule fluorescence in situ hybridization, we demonstrate robust transcript detection possible down to ~100 transcripts per region. To assess the performance of WTA across tissue and sample types, we applied WTA to biological questions in cancer, molecular pathology, and developmental biology. We show that spatial profiling with WTA can detect expected spatial gene expression differences between tumor and tumor microenvironment, identify spatial disease-specific heterogeneity in gene expression in histological structures of the human kidney, and comprehensively map transcriptional programs in anatomical substructures of nine organs in the developing mouse embryo. Digital Spatial Profiling technology with the WTA assays provides a flexible method for spatial whole transcriptome profiling applicable to diverse tissue types and biological contexts.

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5‐Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia

Cited by 35 publications

References 38 publications

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

PSA density is associated with BPH cellular composition

Spatially resolved whole transcriptome profiling in human and mouse tissue using Digital Spatial Profiling

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