Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic induc...

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Bibliographic Details
Published inJCI insight Vol. 9; no. 2
Main Authors Pollack, Anna S, Kunder, Christian A, Brazer, Noah, Shen, Zhewei, Varma, Sushama, West, Robert B, Cunha, Gerald R, Baskin, Laurence S, Brooks, James D, Pollack, Jonathan R
Format Journal Article
LanguageEnglish
Published United States 23.01.2024
Subjects
Adult
Aged
Epithelium - metabolism
Fibroblasts - metabolism
Gene Expression Profiling
Humans
Male
Prostate - metabolism
Prostatic Hyperplasia - genetics
Prostatic Hyperplasia - metabolism
Molecular pathology
Expression profiling
Reproductive Biology
Urology
Cell Biology
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Summary:Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.
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ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.176479