Paracrine Wnt signaling is necessary for prostate epithelial proliferation.

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-CreERT2 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.

The Prostate. 2022 Jan 11 [Epub ahead of print]

Xing Wei, Martine P Roudier, Oh-Joon Kwon, Justin D Lee, Kevin Kong, Ruth Dumpit, Lawrence True, Colm Morrissey, Daniel W Lin, Peter S Nelson, Li Xin

Department of Urology, University of Washington, Seattle, Washington, USA., Molecular Engineering PhD Program, University of Washington, Seattle, Washington, USA., Department of Biology, University of Washington, Seattle, Washington, USA., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

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