RapidCaP, a novel GEM model for analysis and therapy of metastatic prostate cancer, reveals Myc as a driver of Pten-mutant metastasis

Cho, H., Herzka, T., Zheng, W., Qi, J., Wilkinson, J. E., Bradner, J. E., Robinson, B. D., Castillo-Martin, M., Cordon-Cardo, C., Trotman, L. C. (January 2014) RapidCaP, a novel GEM model for analysis and therapy of metastatic prostate cancer, reveals Myc as a driver of Pten-mutant metastasis. Cancer Discovery, 4 (3). pp. 318-33. ISSN 21598274

URL: http://www.ncbi.nlm.nih.gov/pubmed/24444712
DOI: 10.1158/2159-8290.cd-13-0346

Abstract

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 prostate. We show that in Pten-deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by 4 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 show 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > metastasis
organism description > model organism
organism description > animal > mammal > rodent > mouse
organs, tissues, organelles, cell types and functions > organs types and functions > prostate
diseases & disorders > cancer > cancer types > prostate cancer
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Trotman lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date: 27 January 2014
Date Deposited: 04 Feb 2014 15:06
Last Modified: 04 Nov 2015 16:06
PMCID: PMC4084646
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29470

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