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Updated: Aug 23, 2025
Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
Published on: November 22, 2019
Wntless expression promotes lineage plasticity and is associated with neuroendocrine prostate cancer
Leandro S D'Abronzo1, Alan P Lombard1,2,3, Shu Ning1
1Department of Urologic Surgery, University of California Davis Sacramento, California, USA.
Abstract:
Resistance to androgen receptor (AR) targeted therapies remains as the main reason for most prostate cancer related deaths. Lineage plasticity resulting in altered, treatment insensitive prostate tumor cell phenotypes such neuroendocrine differentiated prostate cancer is a common manifestation within resistant tumors upon AR-targeted therapies. The mechanisms responsible for lineage plasticity in prostate cancer remain incompletely understood. Here we demonstrate that the enzalutamide resistant MDVR cell line possesses lineage plastic characteristics associated with overexpression of the Wnt transporter Wntless (WLS). Furthermore, we present evidence that overexpression of WLS is common in varying cell line models of lineage plastic prostate cancer, is higher in neuroendocrine patient samples, and positively correlates with the neuroendocrine marker SYP in clinical data. Targeting WLS in lineage plastic cellular models reduces viability and represses lineage plasticity associated gene expression. Our study provides insight into the importance of WLS to the development of lethal resistant prostate cancer and provides a potential target for the treatment of advanced disease.
Insights
Wntless (WLS) overexpression drives prostate cancer lineage plasticity and resistance to therapy. Targeting WLS may offer a new treatment strategy for advanced, lethal prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Androgen receptor (AR) targeted therapies are standard for prostate cancer but resistance leads to lethal disease.
- Lineage plasticity, particularly neuroendocrine differentiation, is a common mechanism of resistance to AR-targeted therapies.
- The underlying mechanisms driving lineage plasticity in prostate cancer are not fully understood.
Purpose of the Study:
- To investigate the role of Wntless (WLS) in mediating lineage plasticity in prostate cancer.
- To evaluate WLS as a potential therapeutic target for treatment-resistant prostate cancer.
Main Methods:
- Utilized enzalutamide-resistant MDVR cell line models with lineage plastic characteristics.
- Assessed WLS expression in various prostate cancer cell line models and patient samples.
- Correlated WLS expression with neuroendocrine markers (SYP) in clinical data.
- Targeted WLS inhibition in cellular models to assess impact on viability and gene expression.
Main Results:
- Enzalutamide-resistant MDVR cells exhibited lineage plasticity and WLS overexpression.
- WLS overexpression was prevalent in lineage plastic prostate cancer models and higher in neuroendocrine patient samples.
- WLS expression positively correlated with the neuroendocrine marker SYP in clinical data.
- WLS targeting reduced viability and repressed lineage plasticity-associated gene expression in cellular models.
Conclusions:
- Wntless (WLS) plays a significant role in the development of lineage plasticity in prostate cancer.
- WLS is a potential therapeutic target for overcoming resistance to AR-targeted therapies in advanced prostate cancer.
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