Rapid in vivo validation of candidate drivers derived from the PTEN-mutant prostate metastasis genome.

TitleRapid in vivo validation of candidate drivers derived from the PTEN-mutant prostate metastasis genome.
Publication TypeJournal Article
Year of Publication2015
AuthorsCho H, Herzka T, Stahlhut C, Watrud K, Robinson BD, Trotman LC
JournalMethods
Volume77-78
Pagination197-204
Date Published2015 May
ISSN1095-9130
KeywordsAnimals, Genetic Association Studies, Genome, Humans, Male, Mice, Mice, Knockout, Mutation, Prostate, Prostatic Neoplasms, PTEN Phosphohydrolase, Time Factors, Tumor Suppressor Proteins
Abstract

Human genome analyses have revealed that increasing gene copy number alteration is a driving force of incurable cancer of the prostate (CaP). Since most of the affected genes are hidden within large amplifications or deletions, there is a need for fast and faithful validation of drivers. However, classic genetic CaP engineering in mouse makes this a daunting task because generation, breeding based combination of alterations and non-invasive monitoring of disease are too time consuming and costly. To address the unmet need, we recently developed RapidCaP mice, which endogenously recreate human PTEN-mutant metastatic CaP based on Cre/Luciferase expressing viral infection, that is guided to Pten(loxP)/Trp53(loxP) prostate. Here we use a sensitized, non-metastatic Pten/Trp53-mutant RapidCaP system for functional validation of human metastasis drivers in a much accelerated time frame of only 3-4months. We used in vivo RNAi to target three candidate tumor suppressor genes FOXP1, RYBP and SHQ1, which reside in a frequent deletion on chromosome 3p and show that Shq1 cooperates with Pten and p53 to suppress metastasis. Our results thus demonstrate that the RapidCaP system forms a much needed platform for in vivo screening and validation of genes that drive endogenous lethal CaP.

DOI10.1016/j.ymeth.2014.12.022
Alternate JournalMethods
PubMed ID25592467
PubMed Central IDPMC4429512
Grant List1R01 GM101647 / GM / NIGMS NIH HHS / United States
5T32CA148056 / CA / NCI NIH HHS / United States
R01 CA137050 / CA / NCI NIH HHS / United States
P30 CA045508 / CA / NCI NIH HHS / United States
5P30CA045508 / CA / NCI NIH HHS / United States
T32 CA148056 / CA / NCI NIH HHS / United States
Related Faculty: 
Brian Robinson, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700