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Updated: Nov 8, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Anti-androgen therapy induces transcriptomic reprogramming in metastatic castration-resistant prostate cancer in a
Yun Zhao1, Xiaoxia Peng2, Hope Baldwin2
1Department of Cardiac Surgery, Shanghai East Hospital, Tongji University, Shanghai 200092, China; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
Abstract:
Despite recent development of next-generation androgen receptor (AR) antagonists, metastatic castration-resistant prostate cancer (CRPC) remains incurable and requires deeper understanding through studies in suitable animal models. Prostate-specific deletion of Pten and Smad4 in mice recapitulated the disease progression of human prostate adenocarcinoma, including metastasis to lymph nodes and lung. Moreover, Pten/Smad4 tumors fostered an immunosuppressive microenvironment dominated by myeloid-derived suppressor cells (MDSCs). However, the response of Pten/Smad4 tumors to androgen deprivation and anti-androgen therapies has not been described. Here, we report that the combination of surgical castration and enzalutamide treatment in Pten/Smad4 mice slowed down the tumor growth and prolonged the median survival of the mice for 8 weeks. Treatment-naïve and castration-resistant primary tumors exhibited comparable levels of immune infiltrations with the exception of reduced monocytic MDSCs in CRPC. RNA profiling of treatment-naïve and castration-resistant primary tumors revealed largely preserved transcriptome with modest expressional alterations of collagen-related and immune-related genes, among which CC chemokine receptor type 2 (Ccr2) downregulation and predicted negative activation in CRPC was consistent with reduced monocytic MDSC infiltration. Importantly, significant transcriptomic reprograming was observed in lung metastatic CRPC compared with primary CRPC and enriched for immune-related and coagulation-related pathways. At the individual gene level, we validated the expression changes of some of the most upregulated (Cd36, Bmp5, Bmp6, Etv5, Prex2, Ptprb, Egfl6, Itga8 and Cxcl12) and downregulated genes (Cxcl9 and Adamts5). Together, this study uncovers the inherent activity of Pten/Smad4 tumors to progress to CRPC and highlights potentially targetable transcriptomic signatures associated with CRPC metastasis.
Insights
This study shows that Pten/Smad4 prostate tumors in mice can progress to castration-resistant prostate cancer (CRPC). Combination therapy slowed tumor growth, and metastatic CRPC had distinct gene expression changes.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Metastatic castration-resistant prostate cancer (CRPC) remains a significant clinical challenge.
- Animal models are crucial for understanding CRPC progression and developing new therapies.
- The Pten/Smad4 mouse model recapitulates key features of human prostate adenocarcinoma, including metastasis and an immunosuppressive tumor microenvironment.
Purpose of the Study:
- To investigate the response of Pten/Smad4 prostate tumors to androgen deprivation and anti-androgen therapies.
- To characterize the transcriptomic alterations in primary and metastatic CRPC within this model.
- To identify potential therapeutic targets for CRPC.
Main Methods:
- Surgical castration and enzalutamide treatment in Pten/Smad4 mice.
- Analysis of tumor growth and survival.
- Immune cell profiling, focusing on myeloid-derived suppressor cells (MDSCs).
- RNA sequencing of treatment-naïve, castration-resistant primary tumors, and lung metastases.
Main Results:
- Combination therapy of castration and enzalutamide slowed tumor growth and extended survival by 8 weeks.
- Primary CRPC showed reduced monocytic MDSC infiltration compared to treatment-naïve tumors.
- Transcriptomic analysis revealed preserved primary tumor profiles but significant reprogramming in lung metastases, enriched for immune and coagulation pathways.
- Key gene expression changes, including Ccr2 downregulation, were identified in CRPC.
Conclusions:
- Pten/Smad4 deletion drives prostate cancer progression to CRPC with an immunosuppressive microenvironment.
- Androgen deprivation and enzalutamide offer therapeutic benefit but do not cure the disease.
- Metastatic CRPC exhibits distinct transcriptomic signatures, particularly involving immune and coagulation pathways, offering potential targets for future therapies.
