title: Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+Mice.
abstract: Current genetically-engineered mouse melanoma models are often based onTyr::CreERT2-controlled MAPK pathway activation by the BRAFV600Emutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of theTyr::CreERT2system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas inPtenLoxP/LoxP;BrafCA/+mice lacking theTyr::CreERT2allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters inPtenLoxP/LoxP;BrafCA/+mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors inTyr::CreERT2;PtenLoxP/LoxP;BrafCA/+mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. m.deken@nki.nl.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Deken
authors.affiliation: Department of Experimental Animal Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. j.song@nki.nl.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. j.gadiot@nki.nl.
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.affiliation: Division of Medical Oncology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. adbins@gmail.com.
authors.forename: Adriaan D
authors.initials: AD
authors.lastname: Bins
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. p.kroon@nki.nl.
authors.forename: Paula
authors.initials: P
authors.lastname: Kroon
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. i.verbrugge@nki.nl.
authors.forename: Inge
authors.initials: I
authors.lastname: Verbrugge
authors.affiliation: Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. c.blank@nki.nl.|Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. c.blank@nki.nl.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D019426:Integrases / Q000235:genetics*; D007636:Keratoacanthoma / Q000235:genetics* / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: CreERT2; dermal delivery; melanoma