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

2022-09-08

Mejía-Hernández, Javier Octavio

Keam, Simon P

Saleh, Reem

Muntz, Fenella

Fox, Stephen B

Byrne, David

Kogan, Arielle

Pang, Lokman

Huynh, Jennifer

Litchfield, Cassandra

Caramia, Franco

Lozano, Guillermina

He, Hua

You, James M

Sandhu, Shahneen

Williams, Scott G

Haupt, Ygal

Haupt, Sue

Prostate cancer

Journal Article

http://orcid.org/0000-0003-3733-1180

http://orcid.org/0000-0001-9053-9138

http://orcid.org/0000-0002-8292-1895

http://orcid.org/0000-0002-7648-8896

http://orcid.org/0000-0001-8985-4886

http://orcid.org/0000-0003-2484-1712

10.1038/s41419-022-05211-y

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.

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Cell death & disease 2022; 13(9): 777

Cell death & disease