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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• The role of Wilms Tumor 1 (Wt1) in prostate cancer (PCa) is not fully understood.
• Cancer-associated fibroblasts (CAFs) heterogeneity in PCa requires further investigation.

Purpose of the Study:

• To elucidate the function of Wt1 in regulating the transition of normal fibroblasts (NFs) to CAFs in PCa.
• To investigate the Wt1-Spon2 signaling axis in PCa progression.

Main Methods:

• Analysis of public single-cell RNA sequencing (scRNA-seq) and TCGA datasets.
• In vitro mechanistic and functional assays (gene knockdown, transcriptional activation).
• In vivo animal experiments to assess tumorigenesis.

Main Results:

• Identified seven distinct cell types in PCa, highlighting CAF heterogeneity.
• Screening identified Spondin 2 (Spon2) as a key gene in the NF to CAF transition.
• Wt1 was confirmed to transcriptionally activate Spon2, promoting NF to CAF conversion.
• Wt1 knockdown in CAFs reduced Spon2, inhibiting PCa cell metabolism, proliferation, migration, invasion, and promoting apoptosis.
• In vivo studies confirmed the Wt1/Spon2 axis promotes NF to CAF conversion and PCa tumorigenesis.

Conclusions:

• Wt1 promotes PCa progression by activating Spon2, facilitating the conversion of NFs to CAFs.
• The Wt1/Spon2 axis enhances PCa cell metabolism, proliferation, migration, and invasion, while inhibiting apoptosis.
• Targeting the Wt1/Spon2 pathway may offer a therapeutic strategy for prostate cancer.