Department of Urology, University of Washington, Seattle, Washington, USA.
Molecular Engineering PhD Program, University of Washington, Seattle, Washington, USA.
Prostate. 2022 Apr;82(5):517-530. doi: 10.1002/pros.24298. Epub 2022 Jan 11.
The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized.
We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreER mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells.
We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance.
Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.
Wnt 蛋白在许多器官的发育、稳态和疾病进展中发挥着关键作用，包括前列腺。然而，Wnt 蛋白在不同发育阶段的前列腺细胞谱系中的时空表达模式以及在前列腺癌中的表达模式仍未得到充分描述。
我们通过流式细胞术从发育中和成熟的小鼠前列腺中分离出上皮细胞和基质细胞，并测定 Wnt 配体的表达水平。我们使用 Visium 空间基因表达分析来确定 Wnt 配体在小鼠前列腺腺体内的空间分布。通过激光捕获显微镜结合基因表达分析，我们还确定了晚期人类前列腺癌标本中基质和癌细胞中 Wnt 信号成分的表达模式。为了研究基质来源的 Wnt 配体如何影响前列腺的发育和稳态，我们使用 Col1a2-CreER 小鼠模型特异性地在前列腺基质细胞中破坏 Wnt 转运蛋白 Wntless。
我们表明，前列腺基质细胞是几种 Wnt 配体的主要来源。Visium 空间基因表达分析显示 Wnt 配体在前列腺腺体内有明显的空间分布。我们还表明，Wnt 信号成分在原发性和晚期人类前列腺癌的基质区室中高度表达。阻断基质 Wnt 分泌会减弱前列腺上皮细胞的增殖和再生，但不会影响细胞存活和谱系维持。
我们的研究表明，基质来源的 Wnt 配体在前列腺的发育和稳态中起着关键作用。
