Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
J Pathol. 2023 Sep;261(1):85-95. doi: 10.1002/path.6149. Epub 2023 Aug 7.
Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
肺泡 II 型细胞是一种支气管上皮细胞，在肺部中发挥保护作用，并能再生受损的肺上皮细胞。对年轻成人前列腺和尿道的单细胞 RNA 测序 (scRNA-seq) 鉴定出前列腺尿道和收集管中的细胞群，其形态和转录组特征与肺肺泡 II 型细胞相似。我们进一步通过前列腺外周带组织的 scRNA-seq 鉴定出肺泡 II 型细胞样上皮细胞。在这里，我们旨在鉴定并在原位定位前列腺中的肺泡 II 型细胞，包括在前列腺外周带。我们对 5 种肺泡 II 型细胞标志物 (CP、LTF、MMP7、PIGR、SCGB1A1) 进行了显色 RNA 原位杂交，该研究包含（1）非病变器官供体前列腺和（2）前列腺癌患者根治性前列腺切除术标本。我们报告称，外周带中肺泡 II 型细胞基因的表达与炎症有关，仅限于分类为增生性炎症萎缩 (PIA) 中的中间细胞的腔上皮细胞。与非病变前列腺相比，类肺泡细胞在根治性前列腺切除标本中更为丰富，与高级别前列腺癌相关。我们之前报道过 PIA 中的腔上皮细胞很少携带致癌 TMPRSS2:ERG (ERG+) 基因融合，现在我们证明，在向早期腺癌转化的 ERG+PIA 中存在肺泡细胞。最后，从前列腺切除术标本中获得的前列腺上皮类器官表明，类肺泡上皮细胞可以在类器官中建立，并且与基底细胞或嵴细胞相比，在体外抗雄激素定向治疗中，其雄激素信号基因表达特征降低。总体而言，我们的研究在 PIA 中鉴定出了一群类肺泡细胞，并提出这些细胞在支气管上皮细胞中的作用类似。我们的结果进一步表明，炎症驱动了人类前列腺中的谱系可塑性，并且 PIA 中的肺泡细胞可能容易发生致癌转化。
