American Association for Cancer Research
21598290cd130346-sup-suppl_figure_s3.pdf (807.09 kB)

Supplementary Figure 3 from RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis

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journal contribution
posted on 2023-04-03, 20:45 authored by Hyejin Cho, Tali Herzka, Wu Zheng, Jun Qi, John E. Wilkinson, James E. Bradner, Brian D. Robinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Lloyd C. Trotman

PDF file 152K, Histological analysis reveals characteristics of metastasis in RapidCaP



Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a “MYC-switch” away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance.Significance: The RapidCaP system introduces fast and flexible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN-deficient lethal prostate cancer. Cancer Discov; 4(3); 318–33. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 259

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