Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss

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 value of our models are their intact repertoire of immune cells, which 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. Temporal (12 weeks old vs end point) comparative gene expression profiling analysis of 3' RNA-seq data for anterior prostate tumour tissue of mice with different genotypes. Pten(-/-)Trp53(+/+): 12-weeks old mice n=3 and endpoint mice n=4; Pten(-/-)Trp53(-/-): 12-weeks old mice n=3 and endpoint mice n=3; Pten(-/-)Trp53(R172H/R172H): 12-weeks old mice n=3 and endpoint mice n=3; Pten(-/-)Trp53(R245W/R245W): 12-weeks old mice n=3 and endpoint mice n=3.