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Updated: Oct 3, 2025
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice
Maximilian Marhold1,2, Simon Udovica3, Thais Topakian1,2
1Division of Oncology, Department for Medicine I, Medical University of Vienna, A-1090 Vienna, Austria.
Abstract:
Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions.
Insights
Advanced prostate cancer (PCa) often shows primary resistance to antiandrogen treatments. In the TRAMP model, basal prostate cancer cells and MALAT1 gene fusions drive this resistance by regulating the androgen receptor (AR).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Advanced prostate cancer (PCa) treatment relies on targeting testosterone signaling via androgen deprivation therapy (ADT) or antiandrogen drugs.
- While initially effective, most patients eventually develop resistance, leading to disease progression.
Purpose of the Study:
- To investigate the underlying mechanisms of primary resistance to antiandrogen therapy in prostate cancer.
- To identify specific cell populations and molecular drivers contributing to treatment resistance in the TRAMP mouse model.
Main Methods:
- Utilized the TRAMP mouse model, a well-established model for aggressive prostate cancer.
- Isolated primary tumor cells for organoid culture and characterized basal and luminal cell populations.
- Employed RNA sequencing, Western blotting, and quantitative real-time PCR to analyze molecular signatures and treatment effects.
- Studied the impact of androgen withdrawal and enzalutamide treatment on TRAMP organoids.
Main Results:
- TRAMP basal and luminal cells displayed distinct molecular profiles and generated organoids with different phenotypes.
- TRAMP cells demonstrated primary resistance to antiandrogen treatment, with basal cell-derived organoids showing more pronounced resistance.
- Identified MALAT1 gene fusions as key drivers of antiandrogen resistance by regulating the androgen receptor (AR).
Conclusions:
- TRAMP tumor cells inherently possess primary resistance to androgen inhibition.
- Basal cell function and MALAT1 gene fusions significantly enhance this resistance in advanced prostate cancer.
- Findings highlight potential therapeutic targets for overcoming antiandrogen resistance in prostate cancer.
