RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis.
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.
1Cold Spring Harbor Laboratory, Cancer Center, Cold Spring Harbor; 2Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College; 3Mount Sinai School of Medicine, New York, New York; 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 5Unit for Laboratory Animal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan.
Hyejin
H
Cho
Tali
T
Herzka
Wu
W
Zheng
Jun
J
Qi
John E
JE
Wilkinson
James E
JE
Bradner
Brian D
BD
Robinson
Mireia
M
Castillo-Martin
Carlos
C
Cordon-Cardo
Lloyd C
LC
Trotman
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C561695:(+)-JQ1 compound; D001381:Azepines; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase