Related Experiment Video
Updated: Aug 29, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and
Javier Octavio Mejía-Hernández1,2,3,4, Simon P Keam1,2,3,5, Reem Saleh1,2,3
1Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.
Abstract:
Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.
Insights
New genetically engineered mouse models mimic human prostate cancer, focusing on mutations common in young men. These models highlight the tumor suppressor p53
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Prostate cancer research is hindered by a lack of suitable preclinical animal models.
- Understanding early-stage prostate cancer, especially in younger men, is crucial for improving survival rates.
Purpose of the Study:
- To develop genetically engineered mouse models that accurately mimic human prostate cancer, particularly focusing on driver gene mutations relevant to aggressive forms in young men.
- To investigate the role of the tumor suppressor p53 in prostate cancer development and progression within these novel models.
- To explore the impact of specific p53 mutations on immune cell profiles and their implications for disease progression.
Main Methods:
- Generation of genetically engineered mice with prostate cancer initiated from gland epithelia.
- Selection of driver gene mutations relevant to aggressive prostate cancers in young men.
- Utilizing isogenic hotspot p53 amino acid mutations (R172H and R245W) to study their specific effects.
Main Results:
- The developed mouse models successfully mimic human prostate cancer, retaining intact immune cell repertoires.
- Tumor suppressor p53 plays a critical role in restraining cancer pathways, including cell cycle progression, metabolic alterations, and epithelial-to-mesenchymal transition.
- Specific p53 alterations were found to dictate distinct and temporal changes in immune cell profiles, influencing disease progression.
- Individual p53 mutations (R172H and R245W) drive unique cellular changes affecting proliferation and immunity, supporting a gain-of-function hypothesis.
Conclusions:
- The novel orthotopic mouse models provide critical insights into prostate cancer development and the role of the immune system.
- These models demonstrate that p53 mutations are central to prostate cancer initiation and progression by affecting key cellular pathways.
- The findings suggest that specific p53 mutations confer unique oncogenic functions, impacting tumor behavior and immune response, which has implications for targeted therapies, including immunotherapies.
