WLS-Wnt signaling promotes neuroendocrine prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer.
• The molecular drivers of NEPC development and progression are not fully understood.
• Androgen receptor (AR) targeting in castration-resistant prostate cancer (CRPC) can lead to NEPC.

Purpose of the Study:

• To investigate the role of Wntless (WLS) in the pathogenesis of NEPC.
• To elucidate the molecular mechanisms by which WLS contributes to NEPC.
• To evaluate WLS as a potential therapeutic target for NEPC.

Main Methods:

• Investigated WLS as a transcriptional target of AR.
• Analyzed the activation of the ROR2/PKCδ/ERK signaling pathway.
• Examined WLS expression in clinical prostate cancer samples and datasets.
• Assessed the efficacy of the Wnt secretion inhibitor LGK974 in NE prostate tumor xenografts.

Main Results:

• Wntless (WLS) was identified as a major driver of NEPC and aggressive tumor growth.
• WLS activates the ROR2/PKCδ/ERK pathway, supporting NE traits and proliferation in NEPC cells.
• WLS is highly expressed in CRPC and NEPC tumors.
• LGK974 treatment inhibited the growth of NE prostate tumor xenografts in mice.

Conclusions:

• WLS plays a critical role in NEPC pathogenesis and tumor progression.
• Targeting WLS may represent a viable therapeutic strategy for patients with NEPC.
• WLS-mediated signaling pathways are crucial for maintaining NEPC characteristics.