Locally invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging

Abstract

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

“…To elucidate the mechanistic basis for limited anti-cancer efficacy of dual PI3K/AKT axis and androgen blockade, we performed a pre-clinical trial of degarelix (ADT), with and without copanlisib (pan-PI3K inhibitor) in the castrate-resistant prostate-specific PTEN/p53-deficient genetically engineered mouse model (GEMM) ( 40 ), which recapitulated the modest anti-tumor responses observed in mCRPC patients ( 39 ). Importantly, we discovered that the recruitment of PD-1 expressing tumor-associated macrophages (TAM) limits the phagocytosis mediated-anti-tumor efficacy elicited by ADT/copanlisib combination treatment.…”

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

“…An advanced model with a Cre-activatable luciferase reporter enabled live imaging of disease development. Tumours developed with a sarcomatoid histology and invaded locally to the peritoneal cavity, which did not spread to lymph nodes or distant sites [ 23 ]. While these models have the advantage of orthotopic development and are not immune compromised (in contrast to xenotransplants, for example of patient derived xenografts), they are severely limited by an inadequate modelling of the nature of the driver mutation; where mCRPC is frequently mediated by TP53 missense mutation, rather than its loss.…”