MP39-05 TRANSPOSON MUTAGENESIS DRIVES RENAL CYST FORMATION IN VIVO WHEN COMBINED WITH C-MET HYPERACTIVATION: IMPLICATIONS FOR ACQUIRED RENAL CYSTIC DISEASE

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I1 Apr 2017MP39-05 TRANSPOSON MUTAGENESIS DRIVES RENAL CYST FORMATION IN VIVO WHEN COMBINED WITH C-MET HYPERACTIVATION: IMPLICATIONS FOR ACQUIRED RENAL CYSTIC DISEASE Jason Scovell, Juan Hernandez, Adam Hollander, and Richard Link Jason ScovellJason Scovell More articles by this author , Juan HernandezJuan Hernandez More articles by this author , Adam HollanderAdam Hollander More articles by this author , and Richard LinkRichard Link More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1179AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Acquired renal cystic disease (ARCD) imparts a high risk for renal cell carcinoma (8%) in patients with end-stage renal disease. The molecular mechanism of cyst formation in ARCD remains unknown, although increased hepatocyte growth factor / C-MET signaling have been implicated in cyst formation. To explore molecular mechanisms of renal cyst development relevant to ARCD, we developed a murine model system based on tissue-selectable C-Met activation and transposon-mediated mutagenesis. METHODS To allow conditional activation of C-Met signaling, we engineered a tandem duplicated and mutated human C-MET coding sequence. Cre recombinase catalyzes exchange of the wild type C-Met locus with a constitutively active variant (M1248T). C-met+/M1248T mice were crossed with mice carrying the mutagenic Sleeping Beauty (Onc2) transposable element activated by a cre-dependent transposase (trpase). Localization to the renal epithelium was achieved by ggt-cre. Mice with activated C-Met and transposon mutagenesis (1: c-met+/M1248T; Onc2+/-, trpase+/-; ggt-cre+/-) were compared to mice with activated C-Met (2: c-met+/M1248T; ggt-cre+/-) or activated transposon mutagenesis (3: Onc2+/-, trpase+/-; ggt-cre+/-) alone. Mice were serial imaged by ultrasound and MRI. All kidneys were then examined grossly and histologically at necropsy after aging. RESULTS All mice (N=5) with both C-Met hyperactivation and transposon activity (1) developed large renal cysts by 6 months. No mice with only C-Met hyper-activation (2; N=10) or transposon activity (3; N=10) developed cysts by 6 months. Histological analysis demonstrated fluid filled and hemorrhagic renal cysts without evidence for malignancy. CONCLUSIONS C-Met hyperactivation is insufficient to drive renal cyst formation in isolation. Combining M1248T with transposon mutagenesis drove renal cyst formation with 100% penetrance. By mapping transposon insertion sites in cyst-lining epithelial cells in this model, we can now begin to isolate these interacting genes, which may improve our understanding of the molecular mechanisms underlying ARCD. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e494-e495 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jason Scovell More articles by this author Juan Hernandez More articles by this author Adam Hollander More articles by this author Richard Link More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...