Exploring the Role of <i>Wt1/Spon2</i> Axis in Prostate Cancer Progression and Fibroblast Dynamics

ABSTRACT The role of the transcription factor Wt1 in prostate cancer (PCa) remains unclear. This study utilized public scRNA‐seq datasets and TCGA data to investigate how Wt1 regulates the transition from normal fibroblasts (NFs) to cancer‐associated fibroblasts (CAFs) by activating the Spon2 axis. The results identified seven distinct cell types in PCa tissues through scRNA‐seq annotation, revealing the heterogeneity of CAFs in PCa. Through screening, Spon2 was identified as a key gene involved in the transition from NFs to CAFs. Further upstream transcription factor prediction identified Wt1 as a regulator of Spon2 , and in vitro mechanistic experiments confirmed that Wt1 transcriptionally activates Spon2 , thereby promoting the conversion of NFs into CAFs. In vitro functional assays demonstrated that knocking down Wt1 in CAFs inhibited Spon2 expression, leading to reduced PCa cell metabolism, suppression of proliferation, migration, and invasion, while promoting apoptosis. Moreover, in vivo animal experiments confirmed that activation of the Wt1/Spon2 signaling axis promotes the conversion of NFs to CAFs, thereby enhancing tumorigenesis in PCa cells. In summary, Wt1 promotes the transition of NFs into CAFs by activating Spon2 expression, which enhances PCa cell metabolism, promotes proliferation, migration, and invasion, and inhibits apoptosis, ultimately facilitating PCa tumor growth in vivo.