title: Rapid in vivo validation of candidate drivers derived from the PTEN-mutant prostate metastasis genome.
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.
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Cho
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Tali
authors.initials: T
authors.lastname: Herzka
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Stahlhut
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Watrud
authors.affiliation: Department of Pathology & Laboratory Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, 1300 York Avenue, 525 East 68th Street, New York, NY 10065, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA. Electronic address: trotman@cshl.edu.
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
mesh_terms: D000818:Animals; D056726:Genetic Association Studies / Q000379:methods*; D016678:Genome / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Cancer gene discovery; Mouse models; PTEN; Prostate cancer; RapidCaP; Tumor suppressor screening